Substituted benzazoles and methods of their use as inhibitors of Raf kinase

ABSTRACT

New substituted benzazole compounds, compositions and methods of inhibition of Raf kinase activity in a human or animal subject are provided. The new compounds compositions may be used either alone or in combination with at least one additional agent for the treatment of a Raf kinase mediated disorder, such as cancer.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/511,966, filed Oct. 16, 2003.

FIELD OF THE INVENTION

The present invention relates to new substituted benzazole compounds andpharmaceutically acceptable salts, esters or prodrugs thereof,compositions of the new compounds together with pharmaceuticallyacceptable carriers, and uses of the new compounds, either alone or incombination with at least one additional therapeutic agent, in theprophylaxis or treatment of cancer.

BACKGROUND OF THE INVENTION

The Raf serine/threonine kinases are essential components of theRas/Mitogen-Activated Protein Kinase (MAPK) signaling module thatcontrols a complex transcriptional program in response to externalcellular stimuli. Raf genes code for highly conservedserine-threonine-specific protein kinases which are known to bind to theras oncogene. They are part of a signal transduction pathway believed toconsist of receptor tyrosine kinases, p21 ras, Raf protein kinases, Mek1(ERK activator or MAPKK) kinases and ERK (MAPK) kinases, whichultimately phosphorylate transcription factors. In this pathway Rafkinases are activated by Ras and phosphorylate and activate two isoformsof Mitogen-Activated Protein Kinase Kinase (called Mek1 and Mek2), thatare dual specificity threonine/tyrosine kinases. Both Mek isoformsactivate Mitogen Activated Kinases 1 and 2 (MAPK, also calledExtracellular Ligand Regulated Kinase 1 and 2 or Erk1 and Erk2). TheMAPKs phosphorylate many substrates including transcription factors andin so doing set up their transcriptional program. Raf kinaseparticipation in the Ras/MAPK pathway influences and regulates manycellular functions such as proliferation, differentiation, survival,oncogenic transformation and apoptosis.

Both the essential role and the position of Raf in many signalingpathways have been demonstrated from studies using deregulated anddominant inhibitory Raf mutants in mammalian cells as well as fromstudies employing biochemical and genetic techniques model organisms. Inmany cases, the activation of Raf by receptors that stimulate cellulartyrosine phosphorylation is dependent on the activity of Ras, indicatingthat Ras functions upstream of Raf. Upon activation, Raf-1 thenphosphorylates and activates Mek1, resulting in the propagation of thesignal to downstream effectors, such as MAPK (mitogen-activated proteinkinase) (Crews et al. (1993) Cell 74:215). The Raf serine/threoninekinases are considered to be the primary Ras effectors involved in theproliferation of animal cells (Avruch et al. (1994) Trends Biochem. Sci.19:279).

Raf kinase has three distinct isoforms, Raf-1 (c-Raf), A-Raf, and B-Raf,distinguished by their ability to interact with Ras, to activate MAPKkinase pathway, tissue distribution and sub-cellular localization(Marias et. al., Biochem. J. 351: 289-305, 2000; Weber et al., Oncogene19:169-176, 2000; Pritchard et al., Mol. Cell. Biol. 15:6430-6442,1995). Raf kinases are activated by Ras and phosphorylate and activatetwo isoforms of Mitogen-Activated Protein Kinase Kinase (called Mek1 andMek2) that are dual specificity threonine/tyrosine kinases. Both Mekisoforms activate Mitogen Activated Kinases 1 and 2 (MAPK, also calledExtracellular Ligand Regulated Kinase 1 and 2 or Erk1 and Erk2). TheMAPKs phosphorylate many substrates including cytosolic proteins and ETSfamily of transcription factors. Raf kinase participation in theRas/MAPK pathway influences and regulates many cellular functions suchas proliferation, differentiation, survival, cell cycle progression andapoptosis.

Activating mutation of one of the Ras genes can be seen in ˜20% of alltumors and the Raf/MEK/ERK pathway is activated in ˜30% of all tumors(Bos et. al., Cancer Res. 49:4682-4689, 1989) (Hoshino et. al., Oncogene18:813-822, 1999). Recent studies have shown that B-Raf mutation in theskin nevi is a critical step in the initiation of melanocytic neoplasia(Pollock et. al., Nature Genetics 25:1-2, 2002). Furthermore, mostrecent studies have emerged that activating mutation in the kinasedomain of B-Raf occurs in ˜66% of melanomas, 12% of colon carcinoma and14% of liver cancer (Davies et. al., Nature 417:949-954, 2002) (Yuen et.al., Cancer Research 62:6451-6455, 2002) (Brose et. al., Cancer Research62:6997-7000, 2002).

Inhibitors of Raf/MEK/ERK pathway at the level of Raf kinases canpotentially be effective as therapeutic agents against tumors withover-expressed or mutated receptor tyrosine kinases, activatedintracellular tyrosine kinases, tumors with aberrantly expressed Grb2(an adapter protein that allows stimulation of Ras by the Sos exchangefactor) as well as tumors harboring activating mutations of Raf itself.In the early clinical trails inhibitor of Raf-1 kinase that also inhibitB-Raf have shown promise as therapeutic agents in cancer therapy (Crump,Current Pharmaceutical Design 8: 2243-2248, 2002; Sebastien et. al.,Current Pharmaceutical Design 8: 2249-2253, 2002). In addition, anorally administered Raf kinase inhibitor that inhibits both B-Raf andC-Raf, BAY 43-9006, is currently undergoing worldwide clinicalevaluation in phase I and II clinical studies in patients with a varietyof malignancies, including melanomas (Tuveson et al., Cancer Cell 4:95-98, 2003).

Disruption of Raf expression in cell lines through the application ofRNA antisense technology has been shown to suppress both Ras andRaf-mediated tumorigenicity (Kolch et al., Nature 349:416-428, 1991;Monia et al., Nature Medicine 2(6):668-675, 1996). In recent studies,reduction in B-Raf levels with RNA interference in melanoma cellsresulted in a profound inhibition of the MAP kinase cascade, diminishedproliferative capacity, and the inability to supportanchorage-independent cell growth (Tuveson et al., Cancer Cell 4: 95-98,2003).

Several Raf kinase inhibitors have been described as exhibiting efficacyin inhibiting tumor cell proliferation in vitro and/or in vivo assays(see, e.g., U.S. Pat. Nos. 6,391,636, 6,358,932, 6,037,136, 5,717,100,6,458,813, 6,204,467, and 6,268,391). Other patents and patentapplications suggest the use of Raf kinase inhibitors for treatingleukemia (see, e.g., U.S. Pat. Nos. 6,268,391, and 6,204,467, andpublished U.S. patent application Ser. Nos. 20020137774; 20020082192;20010016194; and 20010006975), or for treating breast cancer (see, e.g.,U.S. Pat. Nos. 6,358,932, 5,717,100, 6,458,813, 6,268,391, and6,204,467, and published U.S. patent application Ser. No. 20010014679).

Certain benzazole compounds and their use as Raf kinase inhibitors aredisclosed in WO03082272 and published U.S. patent application Ser. No.20040122237 A1. However, these published applications do not disclosethe carboxamide compounds of the present invention.

SUMMARY OF THE INVENTION

New substituted benzazole compounds and pharmaceutically acceptablesalts thereof or esters having a solubility enhancing moieties orprodrugs thereof are provided of the formula (I):

wherein, X₁ and X₃ are independently selected from N, —NR₄—, —O— or —S—,wherein R₄ is hydrogen or loweralkyl, provided that at least one of X₁and X₃ must be N or —NR₄—;

X₂ is —NH— or —CH₂)_(m)—, wherein m is 0, 1, 2, 3 or 4;

A₁ is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl,aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl,heteroarylaryl, or heteroarylheteroaryl;

R₁ is hydrogen or substituted or unsubstituted loweralkyl, alkoxyalkyl,loweralkyloxy, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, alkyloxyalkylheterocycloalkyl, heteroarylalkyl,cycloalkyloweralkyl, heterocycloalkylloweralkyl,loweralkylheterocycloalkyl, arylloweralkyl, heteroarylloweralkyl,alkyloxyalkylheterocycloloweralkyl, or heteroarylloweralkyl;

R₂ is hydrogen or loweralkyl;

each R₃ and R₃′ are independently selected from hydrogen, halogen,hydroxy, cyano, loweralkyl, or loweralkoxy; and

p and q are independently 0, 1, 2 or 3; or

a pharmaceutically acceptable salt, ester or prodrug thereof.

In other embodiments, new substituted benzimidazole compounds areprovided of the formula (II):

wherein and X₂, A₁, R₁, R₂, R₃, and R₄ are as defined above; or

a pharmaceutically acceptable salt, ester or prodrug thereof.

In other embodiments, new substituted benzazole compounds are providedof the formula (III):

wherein and X₁, X₂, A₁, R₁, R₂, and R₃ are as defined above; or

a pharmaceutically acceptable salt, ester or prodrug thereof.

In other embodiments, new substituted benzazole compounds are providedof the formula (IV):

wherein X₁, A₁, R₁, R₂, and R₃ are as defined above; or

a pharmaceutically acceptable salt, ester or prodrug thereof.

In yet other embodiments, new substituted benzimidazole compounds areprovided of the formula (V):

wherein R₁, R₂, R₃ and R₄ are as defined above; and

R₅, R₆, R₇, R₈ and R₉ are independently selected from hydrogen, halo,loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy,haloloweralkyloxy, loweralkylthio, haloloweralkylthio, and substitutedor unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

a pharmaceutically acceptable salt, ester or prodrug thereof.

In yet other embodiments, new substituted benzimidazole compounds areprovided of the formula (VI):

wherein R₂, R₃, R₄ R₅, R₆, R₇, R₈ and R₉ are as defined above;

n is 0, 1, 2, 3 or 4;

R₁₀, and R₁₂ are independently selected from hydrogen, halo, loweralkyl,haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy,loweralkylsulfonyl, haloloweralkylsulfonyl, and substituted orunsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and

R₁₁ is hydrogen, , loweralkyl, haloloweralkyl, hydroxyloweralkyl,loweralkyloxy, haloloweralkyloxy, loweralkyloxyloweralkyl, andsubstituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; or

a pharmaceutically acceptable salt, ester or prodrug thereof.

In other aspects, the present invention provides methods for treatingRaf related disorders in a human or animal subject in need of suchtreatment comprising administering to said subject an amount of acompound of formula (I), (II), (III), (IV), (V) or (VI) effective toreduce or prevent tumor growth in the subject.

In yet other aspects, the present invention provides methods fortreating Raf related disorders in a human or animal subject in need ofsuch treatment comprising administering to said subject an amount of acompound of formula (I), (II), (III), (IV), (V) or (VI) effective toreduce or prevent tumor growth in the subject in combination with atleast one additional agent for the treatment of cancer.

In yet other aspects, the present invention provides therapeuticcompositions comprising at least one compound of formula (I), (II),(III), (IV), (V) or (VI) in combination with one or more additionalagents for the treatment of cancer, as are commonly employed in cancertherapy.

In yet other aspects, the present invention provides a compound offormula (I), (II), (III), (IV), (V) or (VI) for use as a pharmaceutical.The present invention further provides for the use of a compound offormula (I), (II), (III), (IV), (V) or (VI) in the manufacture of amedicament for the treatment of cancer.

The compounds of the invention are useful in the treatment of cancers,including malignant melanoma, papillary thyroid cancer,cholangiocarcinoma, gallbladder carcinoma, colorectal cancer, lungcancer, pancreatic cancer, leukemias, prostate cancer, ovarian cancer,breast cancer and lung cancer.

The invention further provides compositions, methods of use, and methodsof manufacture as described in the detailed description of theinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

In accordance with one aspect of the present invention, new substitutedbenzazole compounds and pharmaceutically acceptable salts, esters orprodrugs thereof are provided of the formula (I):

wherein, X₁ and X₃ are independently selected from N, —NR₄—, —O— or —S—,wherein R₄ is hydrogen or loweralkyl, provided that at least one of X₁and X₃ must be N or —NR₄—;

X₂ is —NH— or —(CH₂)_(m)—, wherein m is 0, 1, 2, 3 or 4;

A₁ is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl,aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl,heteroarylaryl, or heteroarylheteroaryl;

R₁ is hydrogen or substituted or unsubstituted loweralkyl, alkoxyalkyl,loweralkyloxy, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, alkyloxyalkylheterocycloalkyl, heteroarylalkyl,cycloalkyloweralkyl, heterocycloalkylloweralkyl,loweralkylheterocycloalkyl, arylloweralkyl, heteroarylloweralkyl,alkyloxyalkylheterocycloloweralkyl, or heteroarylloweralkyl;

R₂ is hydrogen or loweralkyl;

each R₃ and R₃′ are independently selected from hydrogen, halogen,hydroxy, cyano, loweralkyl, or loweralkoxy; and

p and q are independently 0, 1, 2 or 3; or

a pharmaceutically acceptable salt, ester or prodrug thereof.

In some aspects of the invention, X₁ in formula (I) is —NR₄—. Thus, insome embodiments, new substituted benzimidazole compounds are providedof the formula (II):

wherein and X₂, A₁, R₁, R₂, R₃, and R₄ are as defined above; or

a pharmaceutically acceptable salt, ester or prodrug thereof.

In other embodiments of the invention, X₃ is N and X₄, is —CH— informula (I). Thus, in some aspects the invention provides newsubstituted benzazole compounds of the formula (III):

wherein and X₁, X₂, A₁, R₁, R₂, and R₃ are as defined above; or

a pharmaceutically acceptable salt, ester or prodrug thereof.

In other embodiments of the invention, X₂ is —NH— in formula (I). Thus,in some aspects, new substituted benzazole compounds are provided of theformula (IV):

wherein X₁, A₁, R₁, R₂, and R₃ are as defined above; or

a pharmaceutically acceptable salt, ester or prodrug thereof.

In yet other embodiments of the invention, X₁ —NR₄—, X₂ is —NH—, X3 isN, X₄ is —CH— and A₁ is in formula (I) has the structure:

wherein R₅, R₆, R₇, R₈ and R₉ are independently selected from hydrogen,halo, loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy,haloloweralkyloxy, loweralkylthio, haloloweralkylthio, and substitutedor unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.Thus, in some aspects, new substituted benzimidazole compounds areprovided of the formula (V):

wherein R₁, R₂, R₃ and R₄ are as defined above; and

R₅, R₆, R₇, R₈ and R₉ are independently selected from hydrogen, halo,loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy,haloloweralkyloxy, loweralkylthio, haloloweralkylthio, and substitutedor unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

a pharmaceutically acceptable salt, ester or prodrug thereof. Inrepresentative, but non-limiting embodiments, R₅, R₆, R₇, R₈ and R₉ maybe independently selected from, for example, hydrogen, chloro, fluoro,methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, methyloxy,trifluoromethyl, trifluoromethoxy, trifluoromethylthio, acetyl, andsubstituted or unsubstituted phenyl, phenyloxy, furyl,tetrahydrofuranyl, tetrahydropyranyl, pyridinyl,trifluoromethylpiperidinyl, thiophenyl, piperazinyl, and morpholinyl.

In yet other embodiments, R₁ in formula (V) has the structure:

wherein n is 0, 1, 2, 3 or 4;

r is 1 or 2;

X₄ is —CH— or N

R₁₀, and R₁₂ are independently selected from hydrogen, halo, loweralkyl,haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy,loweralkylsulfonyl, haloloweralkylsulfonyl, and substituted orunsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and

R₁₁ is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl,loweralkyloxy, haloloweralkyloxy, loweralkyloxyloweralkyl, andsubstituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, orheteroaryl. In some presently preferred embodiments, r is 1 and X₄ is N.Thus, in some aspects the invention provides new substitutedbenzimidazole compounds are provided of the formula (VI):

wherein R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are as defined above;

n is 0, 1, 2, 3 or 4;

R₁₀, and R₁₂ are independently selected from hydrogen, halo, loweralkyl,haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy,loweralkylsulfonyl, haloloweralkylsulfonyl, and substituted orunsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and

R₁₁ is hydrogen, , loweralkyl, haloloweralkyl, hydroxyloweralkyl,loweralkyloxy, haloloweralkyloxy, loweralkyloxyloweralkyl, andsubstituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; or

a pharmaceutically acceptable salt, ester or prodrug thereof.

In another aspect, the present invention provides methods of treatinghuman or animal subjects suffering from a Raf related disorder, such ascancer. Thus, the present invention provides methods of treating a humanor animal subject in need of such treatment comprising administering tothe subject a therapeutically effective amount of a compound of formula(I), (II), (III), (IV), (V) or (VI) above, either alone or incombination with other anticancer agents.

In other aspects, the present invention provides methods for treatingRaf related disorders in a human or animal subject in need of suchtreatment comprising administering to said subject an amount of acompound of formula (I), (II), (III), (IV) or (V) effective to reduce orprevent tumor growth in the subject.

In yet other aspects, the present invention provides methods fortreating Raf related disorders in a human or animal subject in need ofsuch treatment comprising administering to said subject an amount of acompound of formula (I), (II), (III), (IV) or (V) effective to reduce orprevent tumor growth in the subject in combination with at least oneadditional agent for the treatment of cancer. A number of suitableanticancer agents to be used as combination therapeutics arecontemplated for use in the methods of the present invention. Indeed,the present invention contemplates, but is not limited to,administration of numerous anticancer agents such as: agents that induceapoptosis; polynucleotides (e.g., ribozymes); polypeptides (e.g.,enzymes); drugs; biological mimetics; alkaloids; alkylating agents;antitumor antibiotics; antimetabolites; hormones; platinum compounds;monoclonal antibodies conjugated with anticancer drugs, toxins, and/orradionuclides; biological response modifiers (e.g. interferons [e.g.IFN-a, etc.] and interleukins [e.g. IL-2, etc.], etc.); adoptiveimmunotherapy agents; hematopoietic growth factors; agents that inducetumor cell differentiation (e.g. all-trans-retinoic acid, etc.); genetherapy reagents; antisense therapy reagents and nucleotides; tumorvaccines; inhibitors of angiogenesis, and the like. Numerous otherexamples of chemotherapeutic compounds and anticancer therapies suitablefor coadministration with the disclosed compounds of formula (I), (II),(III), (IV), (V) or (VI) are known to those skilled in the art.

In preferred embodiments, anticancer agents to be used in combinationwith compounds of the present invention comprise agents that induce orstimulate apoptosis. Agents that induce apoptosis include, but are notlimited to, radiation; kinase inhibitors (e.g., epidermal growth factorreceptor [EGFR] kinase inhibitor, vascular endothelial growth factorreceptor [VEGFR] kinase inhibitor, fibroblast growth factor receptor[FGFR] kinase inhibitor, platelet-derived growth factor receptor [PGFR]I kinase inhibitor, and Bcr-Abl kinase inhibitors such as Gleevec®[imatinib mesylate or STI-571]); antisense molecules; antibodies [e.g.,Herceptin® anti-HER monoclonal antibody and Rituxan® anti-CD20monoclonal antibody]; anti-estrogens [e.g., raloxifene and tamoxifen];anti-androgens [e.g., flutamide, bicalutamide, finasteride,aminoglutethamide, ketoconazole, and corticosteroids]; cyclooxygenase 2(COX-2) inhibitors [e.g., Celecoxib®, meloxicam, NS-398, andnon-steroidal antiinflammatory drugs (NSAIDs)]; and cancerchemotherapeutic drugs [e.g., irinotecan (Camptosar®), CPT-11,fludarabine (Fludara®), dacarbazine (DTIC®), dexamethasone,mitoxantrone, Mylotarg®, VP-16, cisplatinum, 5-FU, doxrubicin, docetaxel(Taxotere® or taxol, dacarbazine, aldesleukin, capecitabine, and Iressa®(gefitinib)]; cellular signaling molecules; ceramides and cytokines; andstaurosprine, and the like.

In some embodiments of this aspect of the invention, anticancer agentsto be used in combination with compounds of the present inventioninclude, for example, dacarbazine, irinotecan, topotecan, gemcitabine,5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes,tezacitabine, cyclophosphamide, vinca alkaloids, imatinib,anthracyclines, rituximab and trastuzumab

In other aspects, the present invention provides pharmaceuticalcompositions comprising at least one compound of formula I, II, III, IVor V together with a pharmaceutically acceptable carrier suitable foradministration to a human or animal subject, either alone or togetherwith other anticancer agents.

In other aspects, the present invention provides methods of manufactureof compounds of formula (I), (II), (III), (IV), (V) or (VI) as describedherein.

In yet other aspects, the present invention provides compounds which areinhibitors of the enzyme raf kinase. Since the enzyme is a downstreameffector of p21^(ras), the instant inhibitors are useful inpharmaceutical compositions for human or veterinary use where inhibitionof the raf kinase pathway is indicated, e.g., in the treatment of tumorsand/or cancerous cell growth mediated by raf kinase. In particular, thecompounds are useful in the treatment of human or animal, e.g., murinecancer, since the progression of these cancers is dependent upon the rasprotein signal transduction cascade and therefore is susceptible totreatment by interruption of the cascade by inhibiting raf kinaseactivity. Accordingly, the compounds of the invention are useful intreating cancers, such as, for example, malignant melanoma, papillarythyroid cancer, cholangiocarcinoma, gallbladder carcinoma, colorectalcancer, lung cancer, pancreatic cancer, leukemias, prostate cancer,ovarian cancer, breast cancer and lung cancer.

“Raf inhibitor” is used herein to refer to a compound that exhibits anIC₅₀ with respect to Raf Kinase activity of no more than about 100 μMand more typically not more than about 50 μM, as measured in the Raf/MekFiltration Assay described generally hereinbelow. Preferred isoforms ofRaf Kinase in which the compounds of the present invention will be shownto inhibit, include A-Raf, B-Raf, and C-Raf (Raf-1). “IC₅₀” is thatconcentration of inhibitor which reduces the activity of an enzyme(e.g., Raf kinase) to half-maximal level. Representative compounds ofthe present invention have been discovered to exhibit inhibitoryactivity against Raf. Compounds of the present invention preferablyexhibit an IC₅₀ with respect to Raf of no more than about 10 μM, morepreferably, no more than about 5 μM, even more preferably not more thanabout 1 μM, and most preferably, not more than about 200 nM, as measuredin the Raf kinase assays described herein.

As used herein, the term “benzazoles” includes benzimidazoles,benzothiazoles and benzoxazoles.

The phrase “alkyl” refers to alkyl groups that do not containheteroatoms. Thus the phrase includes straight chain alkyl groups suchas methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl and the like. The phrase also includes branchedchain isomers of straight chain alkyl groups, including but not limitedto, the following which are provided by way of example: —CH(CH₃)₂,—CH(CH₃)(CH₂CH₃), —CH(CH₂CH₃)₂, —C(CH₃)₃, —C(CH₂CH₃)₃, —CH₂CH(CH₃)₂,—CH₂CH(CH₃)(CH₂CH₃), —CH₂CH(CH₂CH₃)₂, —CH₂C(CH₃)₃, —CH₂C(CH₂CH₃),—CH(CH₃)CH(CH₃)(CH₂CH₃), —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH(CH₃)(CH₂CH₃),—CH₂CH₂CH(CH₂CH₃)₂, —CH₂CH₂C(CH₃)₃, —CH₂CH₂C(CH₂CH₃)₃,—CH(CH₃)CH₂—CH(CH₃)₂, —CH(CH₃)CH(CH₃)CH(CH₃)₂,—CH(CH₂CH₃)CH(CH₃)CH(CH₃)(CH₂CH₃), and others. The phrase also includescyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted withstraight and branched chain alkyl groups as defined above. Thus thephrase alkyl groups includes primary alkyl groups, secondary alkylgroups, and tertiary alkyl groups. Preferred alkyl groups includestraight and branched chain alkyl groups and cyclic alkyl groups having1 to 12 carbon atoms.

As used herein “loweralkyl” includes both substituted or unsubstitutedstraight or branched chain alkyl groups having from 1 to 6 carbon atoms.Representative loweralkyl groups include, for example, methyl, ethyl,propyl, isopropyl, n-butyl, tert-butyl, neopentyl, trifluoromethyl,pentafluoroethyl and the like. Loweralkyl groups may be substituted,such as with halo, hydroxy, amino, nitro and/or cyano groups, and thelike. Representative of halo-substituted and hydroxy-substitutedloweralkyl include chloromethyl, trichloromethyl, fluoromethyl,trifluoromethyl, chloroethyl, fluoroethyl, hydroxyethyl,perfluoropentyl, perflurorheptyl and the like. Other suitablesubstituted loweralkyl moieties include, for example, aralkyl,aminoalkyl, aminoaralkyl, carbonylaminoalkyl, alkylcarbonylaminoalkyl,arylcarbonylaminoalkyl, aralkylcarbonylaminoalkyl, aminoalkoxyalkyl andarylaminoalkyl.

“Loweralkoxy” as used herein refers to RO— wherein R is loweralkyl.Representative examples of loweralkoxy groups include methoxy, ethoxy,t-butoxy, trifluoromethoxy and the like.

As used herein, the term “halogen” or “halo” refers to chloro, bromo,fluoro and iodo groups. “Haloalkyl” refers to an alkyl radicalsubstituted with one or more halogen atoms. The term “haloloweralkyl”refers to a loweralkyl radical substituted with one or more halogenatoms. The term “haloalkoxy” refers to an alkoxy radical substitutedwith one or more halogen atoms. The term “haloloweralkoxy” refers to aloweralkoxy radical substituted with one or more halogen atoms. “Amino”refers herein to the group —NH₂. The term “alkylamino” refers herein tothe group —NRR′ where R and R′ are each independently selected fromhydrogen or a lower alkyl. The term “arylamino” refers herein to thegroup —NRR′ where R is aryl and R′ is hydrogen, a lower alkyl, or anaryl. The term “aralkylamino” refers herein to the group —NRR′ where Ris a lower aralkyl and R′ is hydrogen, a loweralkyl, an aryl, or aloweraralkyl.

The term amino acid refers to both alpha and beta amino acids having D-or L-stereochemistry, and includes, but is not limited to, synthetic,non-natural amino acids having side chains other than those found in the20 common amino acids. Non-natural amino acids are commerciallyavailable or may be prepared according to U.S. Pat. No. 5,488,131 andreferences therein. Amino acids may be further substituted to containmodifications to their amino, carboxy, or side chain groups. Thesemodifications include the numerous protecting groups commonly used inpeptide synthesis.

The term “alkoxyalkyl” refers to the group -alk₁-O-alk₂ where alk₁ isalkyl or alkenyl, and alk₂ is alkyl or alkenyl. The term“loweralkoxyalkyl” refers to an alkoxyalkyl where alk₁ is loweralkyl orloweralkenyl, and alk₂ is loweralkyl or loweralkenyl. The term“aryloxyalkyl” refers to the group -alkyl-O-aryl. The term“aralkoxyalkyl” refers to the group -alkylenyl-O-aralkyl, where aralkylis a loweraralkyl.

The term “alkoxyalkylamino” refers herein to the group—NR-(alkoxyalkyl), where R is typically hydrogen, loweraralkyl, orloweralkyl. The term “aaminoloweralkoxyalkyl” refers herein to anaminoalkoxyalkyl in which the alkoxyalkyl is a loweralkoxyalkyl.

The term “aminocarbonyl” refers herein to the group —C(O)—NH₂.“Substituted aminocarbonyl” refers herein to the group —C(O)—NRR′ whereR is loweralkyl and R′ is hydrogen or a loweralkyl. The term“arylaminocarbonyl” refers herein to the group —C(O)—NRR′ where R is anaryl and R′ is hydrogen, loweralkyl or aryl. “aralkylaminocarbonyl”refers herein to the group —C(O)—NRR′ where R is loweraralkyl and R′ ishydrogen, loweralkyl, aryl, or loweraralkyl.

“Aminosulfonyl” refers herein to the group —S(O)₂—NH₂. “Substitutedaminosulfonyl” refers herein to the group —S(O)₂—NRR′ where R isloweralkyl and R′ is hydrogen or a loweralkyl. The term“aralkylaminosulfonlyaryl” refers herein to thegroup-aryl-S(O)₂—NH-aralkyl, where the aralkyl is loweraralkyl.

“Carbonyl” refers to the divalent group —C(O)—.

“Carbonyloxy” refers generally to the group —C(O)—O. Such groups includeesters, —C(O)—O—R, where R is loweralkyl, cycloalkyl, aryl, orloweraralkyl. The term “carbonyloxycycloalkyl” refers generally hereinto both a “carbonyloxycarbocycloalkyl” and a“carbonyloxyheterocycloalkyl”, i.e., where R is a carbocycloalkyl orheterocycloalkyl, respectively. The term “arylcarbonyloxy” refers hereinto the group —C(O)—O-aryl, where aryl is a mono- or polycyclic,carbocycloaryl or heterocycloaryl. The term “aralkylcarbonyloxy” refersherein to the group —C(O)—O-aralkyl, where the aralkyl is loweraralkyl.

The term “sulfonyl” refers herein to the group —SO₂—. “Alkylsulfonyl”refers to a substituted sulfonyl of the structure —SO₂R— in which R isalkyl. Alkylsulfonyl groups employed in compounds of the presentinvention are typically loweralkylsulfonyl groups having from 1 to 6carbon atoms in its backbone structure. Thus, typical alkylsulfonylgroups employed in compounds of the present invention include, forexample, methylsulfonyl (i.e., where R is methyl), ethylsulfonyl (i.e.,where R is ethyl), propylsulfonyl (i.e., where R is propyl), and thelike. The term “arylsulfonyl” refers herein to the group —SO₂-aryl. Theterm “aralkylsulfonyl” refers herein to the group —SO₂-aralkyl, in whichthe aralkyl is loweraralkyl. The term “sulfonamido” refers herein to—SO₂NH₂.

As used herein, the term “carbonylamino” refers to the divalent group—NH—C(O)— in which the hydrogen atom of the amide nitrogen of thecarbonylamino group can be replaced a loweralkyl, aryl, or loweraralkylgroup. Such groups include moieties such as carbamate esters(—NH—C(O)—O—R) and amides —NH—C(O)—O—R, where R is a straight orbranched chain loweralkyl, cycloalkyl, or aryl or loweraralkyl. The term“loweralkylcarbonylamino” refers to alkylcarbonylamino where R is aloweralkyl having from 1 to about 6 carbon atoms in its backbonestructure. The term “arylcarbonylamino” refers to group —NH—C(O)—R whereR is an aryl. Similarly, the term “aralkylcarbonylamino” refers tocarbonylamino where R is a lower aralkyl. As used herein, the term“aminocarbonyl” refers to the divalent group —C(O)—NH— in which thehydrogen atom of the amide nitrogen of the carbonylamino group can bereplaced a loweralkyl, aryl, or loweraralkyl group, as described above.

As used herein, the term “guanidino” or “guanidyl” refers to moietiesderived from guanidine, H₂N—C(═NH)—NH₂. Such moieties include thosebonded at the nitrogen atom carrying the formal double bond (the“2”-position of the guanidine, e.g., diaminomethyleneamino, (H₂N)₂C═NH—)and those bonded at either of the nitrogen atoms carrying a formalsingle bond (the “1-” and/or “3”-positions of the guandine, e.g.,H₂N—C(═NH)—NH—). The hydrogen atoms at any of the nitrogens can bereplaced with a suitable substituent, such as loweralkyl, aryl, orloweraralkyl.

As used herein, the term “amidino” refers to the moieties R—C(═N)—NR′—(the radical being at the “N¹” nitrogen) and R(NR′)C═N— (the radicalbeing at the “N²” nitrogen), where R and R′ can be hydrogen, loweralkyl,aryl, or loweraralkyl.

“Cycloalkyl” refers to a mono- or polycyclic, heterocyclic orcarbocyclic alkyl substituent. Typical cycloalkyl substituents have from3 to 8 backbone (i.e., ring) atoms in which each backbone atom is eithercarbon or a heteroatom. The term “heterocycloalkyl” refers herein tocycloalkyl substituents that have from 1 to 5, and more typically from 1to 4 heteroatoms in the ring structure. Suitable heteroatoms employed incompounds of the present invention are nitrogen, oxygen, and sulfur.Representative heterocycloalkyl moieties include, for example,morpholino, piperazinyl, piperadinyl and the like. Carbocycloalkylgroups are cycloalkyl groups in which all ring atoms are carbon. Whenused in connection with cycloalkyl substituents, the term “polycyclic”refers herein to fused and non-fused alkyl cyclic structures. Examplesof such polycyclic structures include bicyclic compounds having twobridgehead atoms connected by three or more arms. An example of abicyclic structure is bicyclo[2.2.1] heptane, in which the bridgeheadatoms are connected by three arms respectively having two, two, and onecarbon atoms.

The term “substituted heterocycle” or “heterocyclic group” orheterocycle as used herein refers to any 3- or 4-membered ringcontaining a heteroatom selected from nitrogen, oxygen, and sulfur or a5- or 6-membered ring containing from one to three heteroatoms selectedfrom the group consisting of nitrogen, oxygen, or sulfur; wherein the5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3double bonds; wherein the nitrogen and sulfur atom maybe optionallyoxidized; wherein the nitrogen and sulfur heteroatoms maybe optionallyquarternized; and including any bicyclic group in which any of the aboveheterocyclic rings is fused to a benzene ring or another 5- or6-membered heterocyclic ring independently defined above. The term“heterocycle” thus includes rings in which nitrogen is the heteroatom aswell as partially and fully-saturated rings. Preferred heterocyclesinclude, for example: diazapinyl, pyrryl, pyrrolinyl, pyrrolidinyl,pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazoyl, imidazolinyl,imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridazinyl,oxazolyl, oxazolidinyl, isoxazolyl, isoazolidinyl, morpholinyl,thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl,quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,furyl, thienyl, triazolyl and benzothienyl.

Heterocyclic moieties can be unsubstituted or monosubstituted ordisubstituted with various substituents independently selected fromhydroxy, halo, oxo (C═O), alkylimino (RN═, wherein R is a loweralkyl orloweralkoxy group), amino, alkylamino, dialkylamino, acylaminoalkyl,alkoxy, thioalkoxy, polyalkoxy, loweralkyl, cycloalkyl or haloalkyl.

The heterocyclic groups may be attached at various positions as will beapparent to those having skill in the organic and medicinal chemistryarts in conjunction with the disclosure herein.

where R is H or a heterocyclic substituent, as described herein.

Representative heterocyclics include, for example, imidazolyl, pyridyl,piperazinyl, azetidinyl, thiazolyl, furanyl, triazolyl benzimidazolyl,benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, indolyl, naphthpyridinyl, indazolyl, andquinolizinyl.

“Aryl” refers to optionally substituted monocyclic and polycyclicaromatic groups having from 3 to 14 backbone carbon or hetero atoms, andincludes both carbocyclic aryl groups and heterocyclic aryl groups.Carbocyclic aryl groups are aryl groups in which all ring atoms in thearomatic ring are carbon. The term “heteroaryl” refers herein to arylgroups having from 1 to 4 heteroatoms as ring atoms in an aromatic ringwith the remainder of the ring atoms being carbon atoms. When used inconnection with aryl substituents; the term “polycyclic aryl” refersherein to fused and non-fused cyclic structures in which at least onecyclic structure is aromatic, such as, for example, benzodioxozolo(which has a heterocyclic structure fused to a phenyl group, i.e.,

naphthyl, and the like. Exemplary aryl moieties employed as substituentsin compounds of the present invention include phenyl, pyridyl,pyrimidinyl, thiazolyl, indolyl, imidazolyl, oxadiazolyl, tetrazolyl,pyrazinyl, triazolyl, thiophenyl, furanyl, quinolinyl, purinyl,naphthyl, benzothiazolyl, benzopyridyl, and benzimidazolyl, and thelike.

“Aralkyl” refers to an alkyl group substituted with an aryl group.Typically, aralkyl groups employed in compounds of the present inventionhave from 1 to 6 carbon atoms incorporated within the alkyl portion ofthe aralkyl group. Suitable aralkyl groups employed in compounds of thepresent invention include, for example, benzyl, picolyl, and the like.

Representative heteroaryl groups include, for example, those shownbelow. These heteroaryl groups can be further substituted and may beattached at various positions as will be apparent to those having skillin the organic and medicinal chemistry arts in conjunction with thedisclosure herein.

Representative heteroaryl groups include, for example, imidazolyl,pyridyl, piperazinyl, azetidinyl, thiazolyl, triazolyl benzimidazolyl,benzothiazolyl, benzoxazolyl, pyrazolyl and pyrazinyl.

The term “biaryl” refers to a group or substituent to which two arylgroups, which are not condensed to each other, are bound. Exemplarybiaryl compounds include, for example, phenylbenzene, diphenyldiazene,4-methylthio-1-phenylbenzene, phenoxybenzene, (2-phenylethynyl)benzene,diphenyl ketone, (4-phenylbuta-1,3-diynyl)benzene, phenylbenzylamine,(phenylmethoxy)benzene, and the like. Preferred optionally substitutedbiaryl groups include:2-(phenylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,1,4-diphenylbenzene,N-[4-(2-phenylethynyl)phenyl]-2-[benzylamino]acetamide,2-amino-N-[4-(2-phenylethynyl)phenyl]propanamide,2-amino-N-[4-(2-phenylethynyl)phenyl]acetamide,2-(cyclopropylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,2-(ethylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,2-[(2-methylpropyl)amino]-N-[4-(2-phenylethynyl)phenyl]acetamide,5-phenyl-2H-benzo[d]1,3-dioxolene, 2-chloro-1-methoxy-4-phenylbenzene,2-[(imidazolylmethyl)amino]-N-[4-(2-phenylethynyl)phenyl]-acetamide,4-phenyl-1-phenoxybenzene, N-(2-aminoethyl)[4-(2-phenylethynyl)phenyl]-carboxamide,2-{[(4-fluorophenyl)methyl]amino}-N-[4-(2-phenylethynyl)phenyl]acetamide,2-{[(4-methylphenyl)methyl]amino}-N-[4-(2-phenylethynyl)phenyl]acetamide,4-phenyl-1-(trifluoromethyl)benzene, 1-butyl-4-phenylbenzene,2-(cyclohexylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,2-(ethylmethylamino)-N-[4-(2-phenylethynyl)-phenyl]acetamide,2-(butylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,N-[4-(2-phenylethynyl)phenyl]-2-(4-pyridylamino)acetamide,N-[4-(2-phenylethynyl)phenyl]-2-(quinuclidin-3-ylamino)acetamide,N-[4-(2-phenylethynyl)phenyl]pyrrolidin-2-ylcarboxamide,2-amino-3-methyl-N-[4-(2-phenylethynyl)phenyl]butanamide,4-(4-phenylbuta-1,3-diynyl)phenylamine,2-(dimethylamino)-N-[4-(4-phenylbuta-1,3-diynyl)phenyl]-acetamide,2-(ethylamino)-N-[4-(4-phenylbuta-1,3-diynyl)phenyl]acetamide,4-ethyl-1-phenylbenzene, 1-[4-(2-phenylethynyl)phenyl]ethan-1-one,N-(1-carbamoyl-2-hydroxypropyl)[4-(4-phenylbuta-1,3-diynyl)phenyl]carboxamide,N-[4-(2-phenylethynyl)phenyl]propanamide, 4-methoxyphenyl phenyl ketone,phenyl-N-benzamide, (tert-butoxy)-N-[(4-phenylphenyl)methyl]carboxamide,2-(3-phenylphenoxy)ethanehydroxamic acid, 3-phenylphenyl propanoate,1-(4-ethoxyphenyl)-4-methoxybenzene, and[4-(2-phenylethynyl)phenyl]pyrrole.

The term “heteroarylaryl” refers to a biaryl group where one of the arylgroups is a heteroaryl group. Exemplary heteroarylaryl groups include,for example, 2-phenylpyridine, phenylpyrrole,3-(2-phenylethynyl)pyridine, phenylpyrazole,5-(2-phenylethynyl)-1,3-dihydropyrimidine-2,4-dione,4-phenyl-1,2,3-thiadiazole, 2-(2-phenylethynyl)pyrazine,2-phenylthiophene, phenylimidazole, 3-(2-piperazinylphenyl)-furan,3-(2,4-dichlorophenyl)-4-methylpyrrole, and the like. Preferredoptionally substituted heteroarylaryl groups include:5-(2-phenylethynyl)pyrimidine-2-ylamine, 1-methoxy-4-(2-thienyl)benzene,1-methoxy-3-(2-thienyl)benzene, 5-methyl-2-phenylpyridine,5-methyl-3-phenylisoxazole, 2-[3-(trifluoromethyl)phenyl]furan,3-fluoro-5-(2-furyl)-2-methoxy-1-prop-2-enylbenzene,(hydroxyimino)(5-phenyl(2-thienyl))-methane,5-[(4-methylpiperazinyl)methyl]-2-phenylthiophene,2-(4-ethylphenyl)thiophene, 4-methylthio-1-(2-thienyl)benzene,2-(3-nitrophenyl)thiophene,(tert-butoxy)-N-[(5-phenyl(3-pyridyl))methyl]carboxamide,hydroxy-N-[(5-phenyl(3-pyridyl))methyl]-amide,2-(phenylmethylthio)pyridine, and benzylimidazole.

The term “heteroarylheteroaryl” refers to a biaryl group where both ofthe aryl groups are a heteroaryl group. Exemplary heteroarylheteroarylgroups include, for example, 3-pyridylimidazole, 2-imidazolylpyrazine,and the like. Preferred optionally substituted heteroarylheteroarylgroups include: 2-(4-piperazinyl-3-pyridyl)furan,diethyl-(3-pyrazin-2-yl(4-pyridyl))amine, anddimethyl{2-[2-(5-methylpyrazin-2-yl)ethynyl](4-pyridyl)}amine.

“Optionally substituted” or “substituted” refers to the replacement ofone or more hydrogen atoms with a monovalent or divalent radical.Suitable substitution groups include, for example, hydroxyl, nitro,amino, imino, cyano, halo, thio, sulfonyl, thioamido, amidino, imidino,oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido,carboxyl, formyl, loweralkyl, haloloweralkyl, loweralkyamino,haloloweralkylamino, loweralkoxy, haloloweralkoxy, loweralkoxyalkyl,alkylcarbonyl, aminocarbonyl, arylcarbonyl, aralkylcarbonyl,heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl,cyanoalkyl, aryl and the like. The term substituted and unsubstituted,when introducing a list of substituents, is intended to apply to eachmember of that list. For instance the phrase “substituted andunsubstituted aryl, heteroaryl, or alkyl” and the phrase “substitutedand unsubstituted aryl, heteroaryl, and alkyl” is intended to specifyaryl, heteroaryl, and alky groups that are each substituted orunsubstituted.

The substitution group can itself be substituted. The group substitutedonto the substitution group can be carboxyl, halo; nitro, amino, cyano,hydroxyl, loweralkyl, loweralkoxy, aminocarbonyl, —SR, thioamido, —SO₃H,—SO₂R or cycloalkyl, where R is typically hydrogen, hydroxyl orloweralkyl.

When the substituted substituent includes a straight chain group, thesubstitution can occur either within the chain (e.g., 2-hydroxypropyl,2-aminobutyl, and the like) or at the chain terminus (e.g.,2-hydroxyethyl, 3-cyanopropyl, and the like). Substituted substitutentscan be straight chain, branched or cyclic arrangements of covalentlybonded carbon or heteroatoms.

As used herein, the term “carboxy-protecting group” refers to a carbonylgroup which has been esterified with one of the commonly used carboxylicacid protecting ester groups employed to block or protect the carboxylicacid function while reactions involving other functional sites of thecompound are carried out. In addition, a carboxy protecting group can beattached to a solid support whereby the compound remains connected tothe solid support as the carboxylate until cleaved by hydrolytic methodsto release the corresponding free acid. Representativecarboxy-protecting groups include, for example, loweralkyl esters,secondary amides and the like.

As used herein, the term “pharmaceutically acceptable salts” refers tothe nontoxic acid or alkaline earth metal salts of the compounds ofFormula I. These salts can be prepared in situ during the finalisolation and purification of the compounds of Formula I, or byseparately reacting the base or acid functions with a suitable organicor inorganic acid or base, respectively. Representative salts includebut are not limited to the following: acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, cyclopentanepropionate,dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-napthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylproionate, picrate, pivalate, propionate,succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as loweralkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, methanesulfonic acid, succinic acidand citric acid. Basic addition salts can be prepared in situ during thefinal isolation and purification of the compounds of formula (I), orseparately by reacting carboxylic acid moieties with a suitable basesuch as the hydroxide, carbonate or bicarbonate of a pharmaceuticallyacceptable metal cation or with ammonia, or an organic primary,secondary or tertiary amine. Pharmaceutically acceptable salts include,but are not limited to, cations based on the alkali and alkaline earthmetals, such as sodium, lithium, potassium, calcium, magnesium, aluminumsalts and the like, as well as nontoxic ammonium, quaternary ammonium,and amine cations, including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, ethylamine, and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine and the like.

As used herein, the term “pharmaceutically acceptable ester” refers toesters, which hydrolyze in vivo and include those that break downreadily in the human body to leave the parent compound or a saltthereof. Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include formates, acetates, propionates,butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention. The term “prodrug” refers to compounds that are rapidlytransformed in vivo to yield the parent compound of the above formula,for example by hydrolysis in blood. A thorough discussion is provided inT. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14of the A.C.S. Symposium Series, and in Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

The term “cancer” refers to cancer diseases that can be beneficiallytreated by the inhibition of Raf kinase, including, for example, cancerssuch as malignant melanoma, papillary thyroid cancer,cholangiocarcinoma, gallbladder carcinoma, colorectal cancer, lungcancer, pancreatic cancer, leukemias, prostate cancer, ovarian cancer,breast cancer and lung cancer.

In illustrative embodiments of the invention, A₁ may be, for example,phenyl, phenylalkyl, pyridyl, pyrimidinyl, pyridylalkyl,pyrimidinylalkyl, alkylbenzoate, thiophene, thiophene-2-carboxylate,indenyl, 2,3-dihydroindenyl, tetralinyl, trifluorophenyl,(trifluoromethyl)thiophenyl, morpholinyl, N-piperazinyl,N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl,2,3-dihydroindolyl, 1-aceyt1-2,3-dihydroindolyl, cycloheptyl,bicyclo[2.2.1]hept-2-yl, pyrrolidinyl, pyrrolidin-1-yl,pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl,adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl,imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, napththalenyl,benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl,phenylsulfonyl, phenylalkylsulfonyl, 9H-fluoren-1-yl, piperidin-1-yl,piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, furanyl,N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl,hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, and1,4′-bipiperidin-1′-yl, which may be substituted by one or moresubstitutents selected from the group consisting of hydroxyl, nitro,cyano, halo, and substituted or unsubstituted amino, imino, thio,sulfonyl, thioamido, amidino, imidino, oxo, oxamidino, methoxamidino,imidino, guanidino, sulfonamido, carboxyl, formyl, loweralkyl,haloloweralkyl, loweralkyamino, haloloweralkylamino, loweralkoxy,haloloweralkoxy, loweralkoxyalkyl, alkylcarbonyl, aminocarbonyl,loweralkylaminocarbonyl, heterocycloalkylloweralkylaminocarbonyl,carboxylloweralkylaminocarbonyl, arylcarbonyl, aralkylcarbonyl,heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl,cyanoalkyl, aryl and the like. In other embodiments, A₁ may besubstituted phenyl, such as, for example, substituted or unsubstitutedhydroxyphenyl, hydroxyalkylphenyl, alkylphenyl, dialkylphenyl,trialkylphenyl, alkoxyphenyl, dialkoxyphenyl, alkoxyalkylphenyl,halophenyl, dihalophenyl, haloalkylphenyl, haloalkoxyphenyl,alkylhalophenyl, alkoxyhalophenyl, alkylthiophenyl, aminophenyl,nitrophenyl, acetylphenyl, sulfamoylphenyl, biphenyl, alkoxybiphenyl,cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl,morpholinylphenyl, heterocyclylcarbonylphenyl, heterocyclylphenyl,heterocyclylalkylphenyl, furanylphenyl,(1,4′-bipiperidin-1′-ylcarbonyl)phenyl, pyrimidin-5-ylphenyl, andquinolidinylphenyl. In yet other embodiments, A₁ is substituted phenylselected from the group consisting of chlorophenyl, fluorophenyl,bromophenyl, iodophenyl, dichlorophenyl, difluorophenyl, dibromophenyl,fluororchlorophenyl, bromochlorophenyl, trifluoromethylphenyl,trifluoromethoxyphenyl, alkylbromophenyl, trifluoromethylbromophenyl,alkylchlorophenyl, trifluoromethylchlorophenyl, alkylfluorophenyl, andtrifluoromethylfluorophenyl.

In representative embodiments of the invention, the compounds of theinvention include, for example,4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide,4-({2-[(3-chlorophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(4-bromophenyl)-amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(3-chloro-4-fluorophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,N-methyl-4-{[2-(phenylamino)-1H-benzimidazol-6-yl]oxy}pyridine-2-carboxamide,4-[(2-{[4-bromo-2-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide,N-methyl-4-({2-[(2-methylpropyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,4-[(2-{[4-(dimethylamino)naphthalen-1-yl]-amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide,N-methyl-4-({2-[(4-nitrophenyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,N-methyl-4-({2-[(phenylcarbonyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,N-methyl-4-({2-[(phenylmethyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,methyl4-{[6-({2-[(methylamino)carbonyl]pyridin-4-yl}oxy)-1H-benzimidazol-2-yl]amino}benzoate,4-({2-[(4-chlorophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-[(2-{[2-(ethyloxy)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide,N-methyl-4-({2-[(2-morpholin-4-ylethyl)-amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,4-({2-[(4-iodophenyl)-amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,N-methyl-4-[(2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]pyridine-2-carboxamide,4-({2-[(furan-2-ylmethyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(4-bromo-3-methylphenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(4-acetylphenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,N-methyl-4-({2-[(2,4,6-trimethylphenyl)amino]-1H-benzimidazol-6-yl}oxy)pyridine-2-carboxamide,4-[(2-{[4-(1,1-dimethylethyl)phenyl]amino}-1H-benzimidazol-6-yl)oxy]-N-methylpyridine-2-carboxamide,4-({2-[(2-bromophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(3-bromophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,4-({2-[(2-chlorophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide,methyl3-{[6-({2-[(methylamino)carbonyl]pyridin-4-yl}oxy)-1H-benzimidazol-2-yl]amino}thiophene-2-carboxylate,4-({2-[(4-bromophenyl)amino]-1H-benzimidazol-6-yl}oxy)-N-{(3R,5R)-5-[(methyloxy)methyl]pyrrolidin-3-yl}pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide,4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide,N-methyl-4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-ethylpyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-hydroxyethyl)pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N,N-dimethylpyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide,N-(4-bromophenyl)-1-methyl-5-{[2-(pyrrolidin-1-ylcarbonyl)pyridin-4-yl]oxy}-1H-benzimidazol-2-amine,ethyl(3R)-3-(methyloxy)-4-[({4-[(2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-carbonyl)amino]piperidine-1-carboxylate,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[2-(dimethylamino)ethyl]pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(tetrahydrofuran-2-ylmethyl)pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl)pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(piperidin-4-ylmethyl)pyridine-2-carboxamide,5-({2-[(3-aminopyrrolidin-1-yl)carbonyl]pyridin-4-yl}oxy)-N-(4-bromophenyl)-1-methyl-1H-benzimidazol-2-amine,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[1-(diphenylmethyl)azetidin-3-yl]pyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-piperidin-3-ylpyridine-2-carboxamide,4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-(1,3-thiazol-2-yl)pyridine-2-carboxamide,and4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-N-[(1-ethylpyrrolidin-2-yl)methyl]pyridine-2-carboxamide,(4-{2-[(4-bromophenyl)amino]benzothiazol-5-yloxy}(2-pyridyl))-N-methylcarboxamide,(4-{2-[(4-bromophenyl)amino]benzoxazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide,and other representative compounds set forth in the Examples.

In other aspects, the present invention relates to the processes forpreparing the compounds of Formulas (I), (II), (III), (IV), (V) and (VI)and to the synthetic intermediates useful in such processes.

The compounds of the invention comprise asymmetrically substitutedcarbon atoms. Such asymmetrically substituted carbon atoms can result inthe compounds of the invention comprising mixtures of stereoisomers at aparticular asymmetrically substituted carbon atom or a singlestereoisomer. As a result, racemic mixtures, mixtures of diastereomers,as well as single diastereomers of the compounds of the invention areincluded in the present invention. The terms “S” and “R” configuration,as used herein, are as defined by the IUPAC 1974 RECOMMENDATIONS FORSECTION E, FUNDAMENTAL STEREOCHEMISTRY , Pure Appl. Chem. 45:13-30(1976). The terms α and β are employed for ring positions of cycliccompounds. The α-side of the reference plane is that side on which thepreferred substituent lies at the lower numbered position. Thosesubstituents lying on the opposite side of the reference plane areassigned β descriptor. It should be noted that this usage differs fromthat for cyclic stereoparents, in which “α” means “below the plane” anddenotes absolute configuration. The terms α and β configuration, as usedherein, are as defined by the CHEMICAL ABSTRACTS INDEX GUIDE—APPENDIX IV(1987) paragraph 203.

The present invention also relates to the processes for preparing thecompounds of the invention and to the synthetic intermediates useful insuch processes, as described in detail below.

Synthetic Methods

Compounds of the invention containing a benzimidazole core may beprepared via a number of synthetic routes using methods familiar to oneof skill in the art, such as those disclosed in WO03082272 and publishedU.S. patent application Ser. No. 20040122237 A1. One such route is asshown in Scheme I below. The pyridyl ether Ig is formed by coupling4-halopyridine Ic with phenol If under basic conditions. The resultingamide Ig is treated with KOH and bromine to form the pyridyl amine Ihthat may then be coupled with various acids to form amide Ii. Reductionof Ii gives diamine Ij, which may be coupled with variousthioisocyanates to form benzimidazole Ik.

Compounds containing the oxazole structure may similarly be preparedaccording to the methods above or according to other known generalprocedures, such as those disclosed in WO03082272 and published U.S.patent application Ser. No. 20040122237 A1. In addition, Haviv et al.(J. Med. Chem. 1988, 31:1719) describes a procedure for assemblingoxazole cores wherein a hydroxy aniline is treated with ethyl potassiumxanthate. The resulting sulfuryl benzoxazole may then be chlorinated andcoupled with an amine.

Compounds containing a benzothiazole core may also be prepared accordingto known methods, such as those disclosed in WO03082272 and publishedU.S. patent application Ser. No. 20040122237 A1. An ortho-haloamine maybe reacted with a thioisocyanate to form a thiourea. Reduction with NaHthen allows formation of the thiazole ring.

Intermediates for synthesizing benzoxazoles may generally be preparedthrough the following pathway:

The compounds of the invention are useful in vitro or in vivo ininhibiting the growth of cancer cells. The compounds may be used aloneor in compositions together with a pharmaceutically acceptable carrieror excipient. Suitable pharmaceutically acceptable carriers orexcipients include, for example, processing agents and drug deliverymodifiers and enhancers, such as, for example, calcium phosphate,magnesium stearate, talc, monosaccharides, disaccharides, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidinone, lowmelting waxes, ion exchange resins, and the like, as well ascombinations of any two or more thereof. Other suitable pharmaceuticallyacceptable excipients are described in “Remington's PharmaceuticalSciences,” Mack Pub. Co., New Jersey (1991), incorporated herein byreference.

Effective amounts of the compounds of the invention generally includeany amount sufficient to detectably inhibit Raf activity by any of theassays described herein, by other Raf kinase activity assays known tothose having ordinary skill in the art or by detecting an inhibition oralleviation of symptoms of cancer.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. It will beunderstood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination, and the severity of the particular diseaseundergoing therapy. The therapeutically effective amount for a givensituation can be readily determined by routine experimentation and iswithin the skill and judgment of the ordinary clinician.

For purposes of the present invention, a therapeutically effective dosewill generally be a total daily dose administered to a host in single ordivided doses may be in amounts, for example, of from 0.001 to 1000mg/kg body weight daily and more preferred from 1.0 to 30 mg/kg bodyweight daily. Dosage unit compositions may contain such amounts ofsubmultiples thereof to make up the daily dose.

The compounds of the present invention may be administered orally,parenterally, sublingually, by aerosolization or inhalation spray,rectally, or topically in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles as desired. Topical administration may also involve the useof transdermal administration such as transdermal patches orionophoresis devices. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intrasternalinjection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-propanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordi-glycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols, which are solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, cyclodextrins, and sweetening,flavoring, and perfuming agents.

The compounds of the present invention can also be administered in theform of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multi-lamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto a compound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natural and synthetic. Methodsto form liposomes are known in the art. See, for example, Prescott, Ed.,Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p.33 et seq. (1976).

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more other agents used in the treatment of cancer. Representativeagents useful in combination with the compounds of the invention for thetreatment of cancer include, for example, irinotecan, topotecan,gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes,tezacitabine, cyclophosphamide, vinca alkaloids, imatinib (Gleevec),anthracyclines, rituximab, trastuzumab, as well as other cancerchemotherapeutic agents.

The above compounds to be employed in combination with the compounds ofthe invention will be used in therapeutic amounts as indicated in thePhysicians' Desk Reference (PDR) 47th Edition (1993), which isincorporated herein by reference, or such therapeutically useful amountsas would be known to one of ordinary skill in the art.

The compounds of the invention and the other anticancer agents can beadministered at the recommended maximum clinical dosage or at lowerdoses. Dosage levels of the active compounds in the compositions of theinvention may be varied so as to obtain a desired therapeutic responsedepending on the route of administration, severity of the disease andthe response of the patient. The combination can be administered asseparate compositions or as a single dosage form containing both agents.When administered as a combination, the therapeutic agents can beformulated as separate compositions, which are given at the same time ordifferent times, or the therapeutic agents, can be given as a singlecomposition.

Antiestrogens, such as tamoxifen, inhibit breast cancer growth throughinduction of cell cycle arrest, that requires the action of the cellcycle inhibitor p27Kip. Recently, it has been shown that activation ofthe Ras-Raf-MAP Kinase pathway alters the phosphorylation status ofp27Kip such that its inhibitory activity in arresting the cell cycle isattenuated, thereby contributing to antiestrogen resistance (Donovan etal, J. Biol. Chem. 276:40888, 2001). As reported by Donovan et al.,inhibition of MAPK signaling through treatment with MEK inhibitorchanged the phosphorylation status of p27 in hormone refactory breastcancer cell lines and in so doing restored hormone sensitivity.Accordingly, in one aspect, the compounds of formulas (I), (II), (III),(IV) and (V) may be used in the treatment of hormone dependent cancers,such as breast and prostate cancers, to reverse hormone resistancecommonly seen in these cancers with conventional anticancer agents.

In hematological cancers, such as chronic myelogenous leukemia (CML),chromosomal translocation is responsible for the constitutivelyactivated BCR-AB1 tyrosine kinase. The afflicted patients are responsiveto Gleevec, a small molecule tyrosine kinase inhibitor, as a result ofinhibition of Ab1 kinase activity. However, many patients with advancedstage disease respond to Gleevec initially, but then relapse later dueto resistance-conferring mutations in the Ab1 kinase domain. In vitrostudies have demonstrated that BCR-Av1 employs the Raf kinase pathway toelicit its effects. In addition, inhibiting more than one kinase in thesame pathway provides additional protection againstresistance-conferring mutations. Accordingly, in another aspect of theinvention, the compounds of formulas (I), (II), (III), (IV) and (V) areused in combination with at least one additional agent, such as Gleevec,in the treatment of hematological cancers, such as chronic myelogenousleukemia (CML), to reverse or prevent resistance to the at least oneadditional agent.

The present invention will be understood more readily by reference tothe following examples, which are provided by way of illustration andare not intended to be limiting of the present invention.

Representative side chains for use in the compounds of the followingexamples may generally be prepared in accordance with the followingprocedures:

EXAMPLE 1 Synthesis ofN-[4-({2-[(3-tert-butylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide

Step 1:

Triethylamine (5 mL, 35.6 mmol) was added to a stirring suspension ofacid 1a (3.34 g, 11.6 mmol) in dry THF (44 mL) at 0° C. The reaction wasmaintained at 0° C. for 1 h, after which a solution ofisobutylchloroformate (1.8 mL, 13.9 mmol) in dry THF (14 mL) was addeddropwise. After 1 h at 0° C., a solution of sodium azide (2.28 g, 35.1mmol) in water (8 mL) was added and the resulting reaction wasmaintained at 0° C. for 45 min. The reaction solution was concentratedinto an aqueous slurry and partitioned between saturated aqueous NaHCO₃solution and CH₂Cl₂. The phases were separated and the aqueous portionwas extracted with CH₂Cl₂ (3×). The combined organics were washed withbrine and the combined aqueous portions were further extracted withCH₂Cl₂. The combined organic phases were dried (MgSO₄) and concentratedto give 2.71 g (8.6 mmol, 75%) of an orange solid as crude acyl azide.

A suspension of acyl azide (322 mg, 1.02 mol) and t-butanol (0.2 mL,2.09 mmol) in dry toluene (12 mL) was heated to 100° C. and maintainedat that temperature for 1.5 h. The reaction was allowed to cool to rtand then partitioned between saturated aqueous Na₂CO₃ solution andCH₂Cl₂. The phases were separated and the aqueous portion was extractedwith CH₂Cl₂ (3×). The combined organic portions were washed withsaturated aqueous Na₂CO₃ solution (2×) and brine, dried (MgSO₄), andadsorbed onto SiO₂. Purification by flash chromatography (9:1, 4:1, 2:1hexanes-EtOAc) afforded 131 mg (0.36 mmol, 36%) of an orange solid as1b: ¹H NMR (300 MHz, CDCl₃) δ 8.18 (br s, 1 H), 8.12 (d, J=5.8 Hz, 1 H),8.04 (br dd, 1 H), 7.95 (d, J=2.8 Hz, 1 H), 7.53 (d, J=2.2, 1 H), 7.29(dd, J=2.8, 9.1 Hz, 1 H), 6.91 (d, J=9.3 Hz, 1 H), 6.47 (dd, J=2.5, 5.8Hz, 1H), 3.07 (d, J=5.2 Hz, 3 H), 1.49 (s, 9 H).

Step 2:

Trifluoroacetic acid (4 mL) was added to a stirring suspension of BOCcarbamate 1b (181 mg, 0.5 mmol) in CH₂Cl₂ (4 mL). The resulting reactionwas maintained at rt for 3.5 h and was then concentrated. The cruderesidue was suspended in saturated aqueous Na₂CO₃ and extracted withCH₂Cl₂ (3×). The combined organic portions were concentrated and theresulting residue was adsorbed onto SiO₂. Purification by flashchromatography (0.5:99.5, 0.75:99.25, 1:99, 2:98, 5:95 methanol-CH₂Cl₂)gave 94 mg (0.36 mmol, 72%) of a bright orange solid as 1c: ¹H NMR (300MHz, CDCl₃) δ 8.03 (br d, J=3.3 Hz, 1 H), 7.93 (d, J=2.8 Hz, 1 H), 7.92(d, J=5.8 Hz, 1 H), 7.27 (dd, J=2.8, 9.4 Hz, 1 H), 6.89 (d, J=9.3 Hz, 1H), 6.24 (dd, J=2.2, 6.0 Hz, 1 H), 5.92 (d, J=2.2 Hz, 1 H), 4.44 (br s,2 H), 3.05 (d, J=5.0 Hz, 3 H).

Step 3:

Pyridine (0.08 mL, 0.99 mmol) and acetic anhydride (0.04 mL, 0.42 mmol)was added to suspension of 2-aminopyridine 1c (94 mg, 0.36 mmol) in drydioxane (1.7 mL). The resulting reaction mixture was heated to andmaintained at 85° C. for 2 h. The reaction was allowed to cool to rt andwas then partitioned between EtOAc and saturated aqueous Na₂CO₃. Thelayers were separated and the aqueous layer was extracted with EtOAc(3×). The combined organic portions were washed with brine, dried(MgSO₄), and adsorbed onto SiO₂. Purification by flash chromatography(2:1, 1:1, 1:2, 1:3 hexanes-EtOAc) provided 75 mg (0.25 mmol, 69%) of anorange solid as 1d: ¹H NMR (300 MHz, CDCl₃) δ 8.35 (br s, 1 H), 8.10 (d,J=5.8 Hz, 1 H), 8.05 (br d, J=4.4 Hz, 1 H), 7.95 (d, J=2.8 Hz, 1 H),7.76 (br d, J=1.7 Hz 1 H), 7.30 (dd, J=2.7, 9.1 Hz, 1 H), 6.91 (d, J=9.3Hz, 1 H), 6.60 (dd, J=2.5, 5.8 Hz, 1 H), 3.05 (d, J=5.2 Hz, 3 H), 2.16(s, 3 H).

Step 4:

A suspension of acetamide 1d (75 mg, 0.25 mmol) and 10% Pd/C (30 mg,0.03 mmol) in methanol (5 mL) was charged with H₂ and the resultingreaction mixture was maintained under a H₂ atmosphere for 1 h at rt. Themixture was filtered and the remaining solids washed thoroughly withEtOAc and methanol. The combined organic portions were evaporated toafford 60 mg (0.22 mmol, 88%) of a brown residue as the phenylenediamine, which was carried forward without further purification.

The above diamine (60 mg, 0.22 mmol) was dissolved in methanol (3 mL)and a solution of 3-tert-butyl phenylthioisocyanate (62 mg, 0.32 mmol)in methanol was added. The reaction was maintained for 16 h. Pyridine(0.06 mL, 0.74 mmol) was added to the reaction, followed by ferricchloride (45 mg, 0.28 mmol). The resulting dark reaction mixture wasmaintained at rt for 16 h, then suspended in saturated aqueous Na₂CO₃solution, and filtered with Celite. The remaining solids were washedwith EtOAc and the combined filtrate was partitioned and separated. Theaqueous portion was extracted with EtOAc (3×) and the combined organicportions were washed with brine, dried (MgSO₄), and evaporated.Purification by semi-prep HPLC gave 1e as the TFA salt which wasneutralized with saturated aqueous Na₂CO₃ solution and extracted withEtOAc (3×). The combined organic portions were washed with brine andwater, dried (MgSO₄), and evaporated. The resulting residue wasreconstituted as the mono citrate salt: LCMS m/z 430.3 (MH⁺), t_(R)=2.24min.

EXAMPLE 2 Synthesis ofN-[4-({2-[(4-fluoro-3-tetrahydrofuran-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide

Synthesized as described above in Example 1 using3-(2-fluoro-5-isothiocyanatophenyl)-tetrahydro-furan. LCMS m/z 462.2(MH⁺), R_(t) 2.51 min.

EXAMPLE 3 Synthesis ofN-(4-{[1-methyl-2-({4-[(trifluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridin-2-yl)acetamide

Synthesized as described above in Example 1 using4-trifluoromethylthiophenyl isothiocyanate. LCMS m/z 474.2 (MH⁺), R_(t)3.41 min.

EXAMPLE 4 Synthesis ofN-[4-({2-[(4-fluoro-3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide

Synthesized as described above in Example 1 using4-fluoro-3-isopropylphenyl isothiocyanate. LCMS m/z 434.2 (MH⁺), R_(t)3.28 min.

EXAMPLE 5 Synthesis ofN-{4-[(2-{[4-fluoro-3-(3-furyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide

Synthesized as described above in Example 1 using3-(2-fluoro-5-isothiocyanatophenyl)-furan. LCMS m/z 458.3 (MH⁺), R_(t)2.02 min.

EXAMPLE 6 Synthesis ofN-[4-({2-[(4-fluoro-3-tetrahydrofuran-2-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide

Synthesized as described above in Example 1 using2-(2-Fluoro-5-isothiocyanatophenyl)-tetrahydro-furan. LCMS m/z 462.3(MH⁺), R_(t) 1.87 min.

EXAMPLE 7 Synthesis ofN-[4-({2-[(4-chloro-3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-methylpiperidine-4-carboxamide

1. Synthesis of [(4-(2-amino(4-pyridyloxy))-2-nitrophenyl]methylamine

Bromine (1.3 eq) was added dropwise to a solution of potassium hydroxide(10 eq) at −10° C.4-(4-methylamino-3-nitrophenoxy)-pyridine-2-carboxamide (1 eq) was addedfollowed by dioxane and the mixture was heated to 60° C. for one hour.The mixture was then cooled to ambient temperature followed by slowaddition of acetic acid (5 eq). The solution was heated to 60° C. forone hour. The solution was brought to pH=8 with acetic acid.[4-(2-amino(4-pyridyloxy))-2-nitrophenyl]methylamine precipitated as anorange solid on cooling which was collected by filtration and washedwith water and dried. MS: MH⁺=261.

2. Synthesis of1-methyl-N-(4-{[4-(methylamino)-3-nitrophenyl]oxy}pyridin-2-yl)piperidine-4-carboxamide

To a mixture of 1-methylpiperidine-4-carboxylic acid (1 eq) inN,N-dimethyl formamide and N,N-disopropylethylamine (4 eq) was added BOP(2 eq) and the mixture was stirred at ambient temperature untilhomogeneous. To it was added[4-(2-amino(4-pyridyloxy))-2-nitrophenyl]methylamine (1 eq) and theresulting mixture was stirred at 60° C. for 16 h. The reaction mixturewas then concentrated and partitioned between ethyl acetate and water.The organic layer was dried over sodium sulfate and the resulting1-methyl-N-(4-{[4-(methylamino)-3-nitrophenyl]oxy}pyridin-2-yl)piperidine-4-carboxamidewas purified by silica gel chromatography. MS: MH⁺=386.2.

3. Synthesis ofN-(4-{[3-amino-4-(methylamino)phenyl]oxy}pyridin-2-yl)-1-methylpiperidine-4-carboxamide

The mixture containing1-methyl-N-(4-{[4-(methylamino)-3-nitrophenyl]oxy}-pyridin-2-yl)piperidine-4-carboxamidein methanol with catalytic amount of Lindlar's catalyst was hydrogenatedto yieldN-(4-{[3-amino-4-(methylamino)phenyl]oxy}pyridin-2-yl)-1-methylpiperidine-4-carboxamide.MS: MH⁺=356.2.

4. Synthesis ofN-[4-({2-[(4-chloro-3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-methylpiperidine-4-carboxamide

To 4-chloro-3-(methylethyl)benzeneisothiocyanate (1 eq) in methanol wasaddedN-(4-{[3-amino-4-(methylamino)phenyl]oxy}pyridin-2-yl)-1-methylpiperidine-4-carboxamide(1 eq) and the resulting mixture was stirred at ambient temperature for16 h. LC/MS showed formation of the corresponding thiourea. To it inmethanol was then added anhydrous ferric chloride (1.5 eq) and stirredfor 3 h. The reaction mixture was then concentrated to half its volumeand brought to basic pH with saturated sodium carbonate solution. Theaqueous solution was filtered through celite and was then extracted withethyl acetate and the organic layer was washed with brine and dried withsodium sulfate. The crude was then triturated with hot ether with a fewdrops of ethyl acetate to yieldN-N-[4-({2-[(4-chloro-3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-methylpiperidine-4-carboxamide.MS: MH⁺=534.1.

EXAMPLE 8 Synthesis of1-ethyl-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide

1. Synthesis of 1-(ethyl)piperidine-4-carboxylic acid

To ethylpiperidine-4-carboxylate (1 eq) in ethanol was added iodoethane(1.1 eq) and potassium carbonate (2 eq) and the resulting mixture wasrefluxed for 16 h. The mixture was then cooled to room temperature andfiltered. Ethanol was concentrated and partitioned between methylenechloride and water. The organic layer was then washed with saturatedsodium chloride solution, dried with sodium sulfate and concentrated. Toit was then added concentrated hydrochloric acid and water (2:1) and themixture was refluxed for 5 h. The resulting1-(ethyl)piperidine-4-carboxylic acid was then azeotroped with toluene.MS: MH⁺=158.

2. Synthesis of((1-ethyl)(4-piperidyl))-N-{4-{4-(methylamino)-3-nitrophenoxy}(2-pyridyl)}carboxamide

To a mixture of 1-(ethyl)piperidine-4-carboxylic acid (1 eq) inN,N-dimethyl formamide and N,N-disopropylethylamine (4 eq) was added BOP(2 eq) and the mixture was stirred at ambient temperature untilhomogeneous. To it was added[4-(2-amino(4-pyridyloxy))-2-nitrophenyl]methylamine (1 eq) and theresulting mixture was stirred at 60° C. for 16 h. The reaction mixturewas then concentrated and partitioned between ethyl acetate and water.The organic layer was dried over sodium sulfate and the resulting((1-ethyl)(4-piperidyl))-N-{4-[4-(methylamino)-3-nitrophenoxy]}(2-pyridyl))carboxamidewas purified by silica gel chromatography. MS: MH⁺=400.2.

3. Synthesis ofN-[4-{3-amino-4-(methylamino)}phenoxy](2-pyridyl)-(1-ethyl(4-piperidyl))carboxamide

The mixture containing((1-ethyl)(4-piperidyl))-N-{4-[4-(methylamino)-3-nitrophenoxy]}(2-pyridyl))carboxamidein methanol with catalytic amount of Lindlar's catalyst was hydrogenatedto yieldN-[4-{3-amino-4-(methylamino)}phenoxy](2-pyridyl)-(1-ethyl(4-piperidyl))carboxamide.MS: MH⁺=370.2.

4. Synthesis of1-ethyl-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide

To 2-fluoro-5-(trifluoromethyl)benzeneisothiocyanate (1 eq) in methanolwas addedN-[4-{3-amino-4-(methylamino)}phenoxy](2-pyridyl)-(1-ethyl(4-piperidyl))carboxamide(1 eq) and the resulting mixture was stirred at ambient temperature for16 h. LC/MS showed formation of the corresponding thiourea. To this inmethanol was then added anhydrous ferric chloride (1.5 eq) and stirredfor 3 h. The reaction mixture was then concentrated to half its volumeand brought to basic pH with saturated sodium carbonate solution. Theaqueous solution was filtered through celite and was then extracted withethyl acetate and the organic layer was washed with brine and dried withsodium sulfate. The crude was then triturated with hot ether with a fewdrops of ethyl acetate to yield1-ethyl-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide.MS: MH⁺=557.6.

EXAMPLE 9 Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-isopropylpiperidine-4-carboxamide

1. Synthesis of 1-(methylethyl)piperidine-4-carboxylic acid

To ethylpiperidine-4-carboxylate (1 eq) in methanol was added acetone (1eq) and acetic acid (5%) and the resulting mixture was stirred for 2 hat ambient temperature. To it was then added sodium cyanoborohydride (1eq) and continued stirring for 16 h. The mixture was then concentratedand to it was added sodium bicarbonate and was partitioned between ethylacetate and water. The organic layer was dried with sodium sulfate andconcentrated to yield ethyl-1-(methylethyl)piperidine-4-carboxylate. Tothis was then added concentrated hydrochloric acid and water (2:1) andthe mixture was refluxed for 5 h. The resulting1-(methylethyl)piperidine-4-carboxylic acid was then azeotroped withtoluene. MS: MH⁺=172.

2. Synthesis ofN-{4-[4-(methylamino)3-nitrophenoxy](2-pyridyl)}-[1-(methylethyl)(4-piperidyl]carboxamide

To a mixture of 1-(methylethyl)piperidine-4-carboxylic acid (1 eq) inN,N-dimethyl formamide and N,N-disopropylethylamine (4 eq) was added BOP(2 eq) and the mixture was stirred at ambient temperature untilhomogeneous. To it was added[4-(2-amino(4-pyridyloxy))-2-nitrophenyl]methylamine (1 eq) and theresulting mixture was stirred at 60° C. for 16 h. The reaction mixturewas then concentrated and partitioned between ethyl acetate and water.The organic layer was dried over sodium sulfate and the resultingN-{4-[4-(methylamino)3-nitrophenoxy](2-pyridyl)}-[1-(methylethyl)(4-piperidyl]carboxamidewas purified by silica gel chromatography. MS: MH⁺=414.2.

3. Synthesis ofN-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-[1-methylethyl)(4-piperidyl)]carboxamide

The mixture containingN-{4-[4-(methylamino)3-nitrophenoxy](2-pyridyl)}-[1-(methylethyl)(4-piperidyl]carboxamidein methanol with catalytic amount of Lindlar's catalyst was hydrogenatedto yieldN-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-[1-(methylethyl)(4-piperidyl)]carboxamide.MS: MH⁺=384.2.

4. Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-isopropylpiperidine-4-carboxamide

To 2-fluoro-5-(trifluoromethyl)benzeneisothiocyanate (1 eq) in methanolwas addedN-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-[1-(methylethyl)(4-piperidyl)]carboxamide(1 eq) and the resulting mixture was stirred at ambient temperature for16 h. LC/MS showed formation of the corresponding thiourea. To it inmethanol was then added anhydrous ferric chloride (1.5 eq) and stirredfor 3 h. The reaction mixture was then concentrated to half its volumeand brought to basic pH with saturated sodium carbonate solution. Theaqueous solution was filtered through celite and was then extracted withethyl acetate and the organic layer was washed with brine and dried withsodium sulfate. The crude was then triturated with hot ether with a fewdrops of ethyl acetate to yieldN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-isopropylpiperidine-4-carboxamide.MS: MH⁺=571.6.

EXAMPLE 10 Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-(2-methoxyethyl)piperidine-4-carboxamide

1. Synthesis of 1-(2-methoxyethyl)piperidine-4-carboxylic acid

To ethylpiperidine-4-carboxylate (1 eq) in ethanol was added2-bromo-1-methoxyethane (1 eq) and potassium carbonate 2 eq) and theresulting mixture was refluxed for 16 h. The mixture was then filteredand concentrated. To it was then added ethanol and water (3:1) andsodium hydroxide (1 eq) and it was refluxed for 16 h. The resulting1-(2-methoxyethyl)piperidine-4-carboxylic acid was then azeotroped withtoluene. MS: MH⁺=188.

2. Synthesis of[1-(2-methoxyethyl)(4-piperidyl)}-N-{4-[4-(methylamino)-3-nitrophenoxy](2-[pyridyl)}carboxamide

To a mixture of 1-(2-methoxyethyl)piperidine-4-carboxylic (1 eq) inN,N-dimethyl formamide and N,N-disopropylethylamine (4 eq) was added BOP(2 eq) and the mixture was stirred at ambient temperature untilhomogeneous. To it was added[4-(2-amino(4-pyridyloxy))-2-nitrophenyl]methylamine (1 eq) and theresulting mixture was stirred at 60° C. for 16 h. The reaction mixturewas then concentrated and partitioned between ethyl acetate and water.The organic layer was dried over sodium sulfate and the resulting[1-(2-methoxyethyl)(4-piperidyl)}-N-{4-[4-(methylamino)-3-nitrophenoxy](2-[pyridyl)}-carboxamidewas purified by silica gel chromatography. MS: MH⁺=430.2.

3. Synthesis ofN-{4[3-amino-4-(methylamino)phenoxy](2-pyridyl)}[1-(2-methoxyethyl)(4-piperidyl)]carboxamide

The mixture containing[1-(2-methoxyethyl)(4-piperidyl)}-N-{4-[4-(methylamino)-3-nitrophenoxy](2-[pyridyl)}carboxamidein methanol with catalytic amount of Lindlar's catalyst was hydrogenatedto yieldN-{4[3-amino-4-(methylamino)phenoxy](2-pyridyl)}[1-(2-methoxyethyl)(4-piperidyl)]carboxamide.MS: MH⁺=400.2.

4. Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-(2-methoxyethyl)piperidine-4-carboxamide

To 2-fluoro-5-(trifluoromethyl)benzeneisothiocyanate (1 eq) in methanolwas addedN-{4[3-amino-4-(methylamino)phenoxy](2-pyridyl))}[1-(2-methoxyethyl)(4-piperidyl)]carboxamide(1 eq) and the resulting mixture was stirred at ambient temperature for16 h. LC/MS showed formation of the corresponding thiourea. To it inmethanol was then added anhydrous ferric chloride (1.5 eq) and stirredfor 3 h. The reaction mixture was then concentrated to half its volumeand brought to basic pH with saturated sodium carbonate solution. Theaqueous solution was filtered through elite and was then extracted withethyl acetate and the organic layer was washed with brine and dried withsodium sulfate. The crude was then triturated with hot ether with a fewdrops of ethyl acetate to yieldN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-(2-methoxyethyl)piperidine-4-carboxamide.MS: MH⁺=587.6.

EXAMPLE 11 Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-(2-hydroxyethyl)piperidine-4-carboxamide

ToN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-(2-methoxyethyl)piperidine-4-carboxamide(1 eq) in methylene chloride at −78° C. was added 1M borontribromide inmethylene chloride (10 eq) and the resulting mixture and the resultingmixture was stirred at −78° C. for 1 h. It was then brought to ambienttemperature and stirred for 2 h. LC/MS showed formation of the product.The reaction was quenched with saturated sodium carbonate solution at 0°C. The mixture was concentrated and then brought to pH=9. It was thenextracted with ethyl acetate and the organic layer was dried with sodiumsulfate and concentrated and purified on preparative chromatography toyieldN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-(2-hydroxyethyl)-piperidine-4-carboxamide.MS: MH⁺=573.6.

EXAMPLE 12 Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide

1. Synthesis oftert-butyl-4-(N-{4-[4-(methylamino)-3-nitrophenoxy]-2-pyridyl}carbamoyl)piperidinecarboxylate

To a mixture of 1-(tert-butoxy)carbonylpiperidine-4-carboxylic acid (1eq) in N,N-dimethyl formamide and N,N-disopropylethylamine (4 eq) wasadded BOP (2 eq) and the mixture was stirred at ambient temperatureuntil homogeneous. To it was added[4-(2-amino(4-pyridyloxy))-2-nitrophenyl]methylamine (1 eq) and theresulting mixture was stirred at 60° C. for 16 h. The reaction mixturewas then concentrated and partitioned between ethyl acetate and water.The organic layer was dried over sodium sulfate and the resultingtert-butyl-4-(N-{4-[4-(methylamino)-3-nitrophenoxy]-2-pyridyl}carbamoyl)piperidinecarboxylate was purified by silica gel chromatography. MS:MH⁺=472.2.

2. Synthesis oftert-butyl-4-(N-{4-[3-amino-4-(methylamino)phenoxy]-2-pyridylcarbamoyl)piperidinecarboxylate

The mixture containingtert-butyl-4-(N-{4-[4-(methylamino)-3-nitrophenoxy]-2-pyridyl}carbamoyl)piperidinecarboxylate in methanol with catalytic amount of Lindlar'scatalyst was hydrogenated to yieldtert-butyl-4-(N-{4-[3-amino-4-(methylamino)-phenoxy]-2-pyridylcarbamoyl)piperidinecarboxylate. MS: MH⁺=442.2.

3. Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide

To 2-fluoro-5-(trifluoromethyl)benzeneisothiocyanate (1 eq) in methanolwas addedtert-butyl-4-(N-{4-[3-amino-4-(methylamino)phenoxy]-2-pyridylcarbamoyl)piperidinecarboxylate (1 eq) and the resulting mixture was stirred atambient temperature for 16 h. LC/MS showed formation of thecorresponding thiourea. To it in methanol was then added anhydrousferric chloride (1.5 eq) and stirred for 3 h. The reaction mixture wasthen concentrated to half its volume and brought to basic pH withsaturated sodium carbonate solution. The aqueous solution was filteredthrough celite and was then extracted with ethyl acetate and the organiclayer was washed with brine and dried with sodium sulfate. The crude wasthen triturated with hot ether with a few drops of ethyl acetate toyield the product. To it in methylene chloride was then addedtrifluoroacetic acid to yieldN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide.MS: MH⁺=529.5.

EXAMPLE 13 Synthesis of1-acetyl-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide

ToN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide(1 eq) in dioxane and N,N-disopropylethylamine (2 eq) was added aceticanhydride (1 eq) and the resulting mixture was stirred for 1 h.1-acetyl-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamidethus formed was purified by preparative chromatography. MS: MH⁺=571.5.

EXAMPLE 14 Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-3-piperidin-4-ylpropanamide

1. Synthesis oftert-butyl-4-[2-(N-{4-{4-(methylamino)-3-nitrophenoxy]-2-pyridylcarbamol)ethyl]piperidinecarboxylate

To a mixture of 3-{1-[(tert-butyl)oxycarbonyl]-4-piperidyl}propanoicacid (1 eq) in N,N-dimethyl formamide and N,N-disopropylethylamine (4eq) was added BOP (2 eq) and the mixture was stirred at ambienttemperature until homogeneous. To it was added[4-(2-amino(4-pyridyloxy))-2-nitrophenyl]methylamine (1 eq) and theresulting mixture was stirred at 60° C. for 16 h. The reaction mixturewas then concentrated and partitioned between ethyl acetate and water.The organic layer was dried over sodium sulfate and the resultingtert-butyl-4-[2-(N-{4-{4-(methylamino)-3-nitrophenoxy]-2-pyridylcarbamoyl)-ethyl]piperidinecarboxylate was purified by silica gel chromatography. MS:MH⁺=500.2.

2. Synthesis oftert-butyl-4-[2-(N-{4-[3-amino-4-(methylamino)phenoxy]-2-pyridyl}carbamoyl)ethyl]piperidine carboxylate

The mixture containingtert-butyl-4-[2-(N-{4-{4-(methylamino)-3-nitrophenoxy]-2-pyridylcarbamoyl)ethyl]piperidinecarboxylate in methanol with catalytic amount of Lindlar'scatalyst was hydrogenated to yieldtert-butyl-4-[2-(N-{4-[3-amino-4-(methylamino)phenoxy]-2-pyridyl}carbamoyl)ethyl]piperidine carboxylate. MS: MH⁺=470.2.

3. Synthesis ofN-[4-(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl]-3-(4-piperidyl)propanamide

To 2-fluoro-5-(trifluoromethyl)benzeneisothiocyanate (1 eq) in methanolwas addedtert-butyl-4-[2-(N-{4-[3-amino-4-(methylamino)phenoxy]-2-pyridyl}carbamoyl)-ethyl]piperidine carboxylate (1 eq) and the resulting mixture was stirred atambient temperature for 16 h. LC/MS showed formation of thecorresponding thiourea. To it in methanol was then added anhydrousferric chloride (1.5 eq) and stirred for 3 h. The reaction mixture wasthen concentrated to half its volume and brought to basic pH withsaturated sodium carbonate solution. The aqueous solution was filteredthrough celite and was then extracted with ethyl acetate and the organiclayer was washed with brine and dried with sodium sulfate. The crude wasthen triturated with hot ether with a few drops of ethyl acetate toyield the product. To it was then added trifluoroacetic acid to yieldN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-3-piperidin-4-ylpropanamide.MS: MH⁺=557.6.

EXAMPLE 15 Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-3-(1-methylpiperidin-4-yl)propanamide

ToN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-3-piperidin-4-ylpropanamide(1 eq) in methanol was added formalin (2 eq) and acetic acid(5%)followed by sodium cyanoborohydride (2 eq) and the resulting mixture wasstirred at ambient temperature for 3 h. LC/MS showed formation of theproduct. The crude mixture was then concentrated and to it was addedsodium bicarbonate and the resulting mixture was partitioned betweenethyl acetate and water. The organic layer was dried with sodium sulfateand purified by preparative chromatography to yieldN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-3-(1-methylpiperidin-4-yl)propanamide.MS: MH⁺=571.6.

EXAMPLE 16 Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-3-(1-isopropylpiperidin-4-yl)propanamide

1. Synthesis ofN-[4-(2-{[2-fluoro-5-trifluoromethyl)phenyl]amino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-3-[1-(methylethyl)(4-piperidyl)]propanamide

ToN-[4-(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl]-3-(4-piperidyl)propanamide(1 eq) in methanol was added acetone (2 eq) and acetic acid(5%) followedby sodium cyanoborohydride (2 eq) and the resulting mixture was stirredat ambient temperature for 3 h. LC/MS shows formation of the product.The crude mixture was then concentrated and to it was added sodiumbicarbonate and the resulting mixture was partitioned between ethylacetate and water. The organic layer was dried with sodium sulfate andpurified by preparative chromatography to yieldN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-3-(1-isopropylpiperidin-4-yl)propanamide.MS: MH⁺=599.6.

EXAMPLE 17 Synthesis ofN˜1˜-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-N˜2˜-methylglycinamide

1. Synthesis of2-[(tert-butoxy)-N-methylcarbonylamino]-N-{4-[4-(methylamino)-3-nitrophenoxy](2-pyridyl)acetamide

To a mixture of 2-[(tert-butoxy)-N-methylcarbonylamino]acetic acid (1eq) in N,N-dimethyl formamide and N,N-disopropylethylamine (4 eq) wasadded BOP (2 eq) and the mixture was stirred at ambient temperatureuntil homogeneous. To it was added[4-(2-amino(4-pyridyloxy))-2-nitrophenyl]methylamine (1 eq) and theresulting mixture was stirred at 60° C. for 16 h. The reaction mixturewas then concentrated and partitioned between ethyl acetate and water.The organic layer was dried over sodium sulfate and the resulting2-[(tert-butoxy)-N-methylcarbonylamino]-N-{4-[4-(methylamino)-3-nitrophenoxy](2-pyridyl)acetamidewas purified by silica gel chromatography. MS: MH⁺=432.2.

2. Synthesis ofN-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-2-[(tert-butoxy)-N-methylcarbonylamino]acetamide

The mixture containing2-[(tert-butoxy)-N-methylcarbonylamino]-N-{4-[4-(methylamino)-3-nitrophenoxy](2-pyridyl)acetamidein methanol with catalytic amount of Lindlar's catalyst was hydrogenatedtoN-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-2-[(tert-butoxy)-N-methylcarbonylamino]acetamide.MS: MH⁺=402.2.

3. Synthesis ofN˜1˜{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-N˜2˜-methylglycinamide

To 2-fluoro-5-(trifluoromethyl)benzeneisothiocyanate (1 eq) in methanolwas addedN-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-2-[(tert-butoxy)-N-methylcarbonylamino]acetamide(1 eq) and the resulting mixture was stirred at ambient temperature for16 h. LC/MS showed formation of the corresponding thiourea. To it inmethanol was then added anhydrous ferric chloride (1.5 eq) and stirredfor 3 h. The reaction mixture was then concentrated to half its volumeand brought to basic pH with saturated sodium carbonate solution. Theaqueous solution was filtered through celite and was then extracted withethyl acetate and the organic layer was washed with brine and dried withsodium sulfate. The crude was then triturated with hot ether with a fewdrops of ethyl acetate to yield the product. To it in methylene chloridewas then added trifluoroacetic acid to yieldN˜1˜-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-N˜2˜-methylglycinamide.MS: MH⁺=489.4.

EXAMPLE 18 Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-4-morpholin-4-ylbutanamide

1. Synthesis ofN-{4-[4-(methylamino)-3-nitrophenoxy](2-pyridyl)}-4-morpholino-4-ylbutanamide

To a mixture of 4-morpholino-4-ylbutanoic acid (1 eq) in N,N-dimethylformamide and N,N-disopropylethylamine (4 eq) was added BOP (2 eq) andthe mixture was stirred at ambient temperature until homogeneous. To itwas added [4-(2-amino(4-pyridyloxy))-2-nitrophenyl]methylamine (1 eq)and the resulting mixture was stirred at 60° C. for 16 h. The reactionmixture was then concentrated and partitioned between ethyl acetate andwater. The organic layer was dried over sodium sulfate and the resultingN-{4-[4-(methylamino)-3-nitrophenoxy](2-pyridyl)}-4-morpholino-4-ylbutanamidewas purified by silica gel chromatography. MS: MH⁺=416.2.

2. Synthesis ofN-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl))-4-morpholin-4-ylbutanamide

The mixture containingN-{4-[4-(methylamino)-3-nitrophenoxy](2-pyridyl)}-4-morpholino-4-ylbutanamidein methanol with catalytic amount of Lindlar's catalyst was hydrogenatedto yieldN-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl))-4-morpholin-4-ylbutanamide.MS: MH⁺=386.2.

3. Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-4-morpholin-4-ylbutanamide

To 2-fluoro-5-(trifluoromethyl)benzeneisothiocyanate (1 eq) in methanolwas addedN-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl))-4-morpholin-4-ylbutanamide(1 eq) and the resulting mixture was stirred at ambient temperature for16 h. LC/MS showed formation of the corresponding thiourea. To it inmethanol was then added anhydrous ferric chloride (1.5 eq) and stirredfor 3 h. The reaction mixture was then concentrated to half its volumeand brought to basic pH with saturated sodium carbonate solution. Theaqueous solution was filtered through celite and was then extracted withethyl acetate and the organic layer was washed with brine and dried withsodium sulfate. The crude was then triturated with hot ether with a fewdrops of ethyl acetate toN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-pyridin-2-yl}-4-morpholin-4-ylbutanamide.MS: MH⁺=573.6.

EXAMPLE 19 Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-methoxyethyl)piperazin-1-yl]acetamide

1. Synthesis of2-[4-(2-methoxyethyl)piperizinyl]-N-{4-[4-(methylamino-3-nitrophenoxy](2-pyridyl)}acetamide

To 2-chloro-N-{4-[4-(methylamino)-3-nitrophenoxy](2-pyridyl)}acetamide(1 eq) in acetonitrile was added 1-methoxy-2-piperizinylethane (1 eq)and potassium carbonate (2 eq) and the resulting mixture was heated to60° C. for 16 h. It was then concentrated and partitioned between ethylacetate and water. The organic layer was dried with sodium sulfate andconcentrated to give2-[4-(2-methoxyethyl)piperizinyl]-N-{4-[4-(methylamino-3-nitrophenoxy](2-pyridyl)}acetamide.MS: MH⁺=445.2.

2. Synthesis ofN-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-2-[4-(2-methoxyethyl)piperizinyl]acetamide

The mixture containing2-[4-(2-methoxyethyl)piperizinyl]-N-{4-[4-(methylamino-3-nitrophenoxy](2-pyridyl)}acetamidein methanol with catalytic amount of Lindlar's catalyst was hydrogenatedto yieldN-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-2-[4-(2-methoxyethyl)piperizinyl]acetamide.MS: MH⁺=415.2.

3. Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-methoxyethyl)piperazin-1-yl]acetamide

To 2-fluoro-5-(trifluoromethyl)benzeneisothiocyanate (1 eq) in methanolwas addedN-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-2-[4-(2-methoxyethyl)-piperizinyl]acetamide (1 eq) and the resulting mixture was stirred atambient temperature for 16 h. LC/MS showed formation of thecorresponding thiourea. To it in methanol was then added anhydrousferric chloride (1.5 eq) and stirred for 3 h. The reaction mixture wasthen concentrated to half its volume and brought to basic pH withsaturated sodium carbonate solution. The aqueous solution was filteredthrough celite and was then extracted with ethyl acetate and the organiclayer was washed with brine and dried with sodium sulfate. The crude wasthen triturated with hot ether with a few drops of ethyl acetate toyieldN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-methoxyethyl)piperazin-1-yl]acetamide.MS: MH⁺=602.6.

EXAMPLE 20 Synthesis ofN-{4-[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide

ToN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-methoxyethyl)piperazin-1-yl]acetamide(1 eq) in methylene chloride at −78° C. was added 1M borontribromide inmethylene chloride (10 eq) and the resulting mixture was stirred at −78°C. for 1 h. It was then brought to ambient temperature and stirred for 2h. LC/MS showed formation of the product. The reaction was quenched withsaturated sodium carbonate solution at 0° C. The mixture wasconcentrated and then brought to pH=9. It was then extracted with ethylacetate and the organic layer was dried with sodium sulfate andconcentrated and purified on preparative chromatography to yieldN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide.MS: MH⁺=588.6.

EXAMPLE 21 Synthesis ofN-(4-{[2-(4-chlorobenzyl)-1-methyl-1H-benzimidazol-5-yl]oxy}pyridin-2-yl)acetamide

To N-{4-[3-amino-4-(methylamino)phenoxy]}-2-pyridylacetamide (1 eq) intetrahydrofuran added EDC (2 eq) and HOAT (1 eq) andN,N-disopropylethylamine (4 eq) and 2-(4-chlorophenyl)acetic acid (1 eq)and the resulting mixture was stirred at ambient temperature for 16 h.The reaction mixture was then partitioned between ethyl acetate andwater. The organic layer was then dried with sodium sulfate andconcentrated to giveN-{4-[2-(acetylamino)(4-pyridyloxy)]-2-aminophenyl}-2-(4-chlorophenyl)-N-methylacetamide.To it was added acetic acid and the resulting mixture was heated to 60°C. for 4 h. The crude was purified by preparative chromatography to giveN-(4-{[2-(4-chlorobenzyl)-1-methyl-1H-benzimidazol-5-yl]oxy}pyridin-2-yl)acetamide.MS: MH⁺=407.9.

EXAMPLE 22 Synthesis ofN-[4-({2-[(4-chlorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]benzamide

To[5-(2-amino(4-pyridyloxy))-1-methylbenzimidazol-2-yl](4-chlorophenyl)amine(1 eq) in tetrahydrofuran added EDC (2 eq) and HOAT (1 eq) andN,N-disopropylethylamine (4 eq) and benzoic acid (1 eq) and theresulting mixture was stirred at ambient temperature for 16 h. Thereaction mixture was then partitioned between ethyl acetate and water.The organic layer was then dried with sodium sulfate and concentratedand purified by preparative chromatography to to giveN-[4-({2-[(4-chlorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]benzamide.MS: MH⁺=470.9.

EXAMPLE 23 Synthesis ofN-[4-({2-[(3-tert-butylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N′-(2-morpholin-4-ylethyl)urea

Step 1: Synthesis ofN-{4-[4-(methylamino)-3-nitrophenoxy](2-pyridyl)}[(2-morpholin-4-ylethyl)amino]carboxamide

A flame dried flask was charged with4-[4-(methylamino)-3-nitrophenoxy]-pyridine-2-carboxylic acid (1 eq),diphenylphosphoryl azide (1.1 eq), triethylamine (2.1 eq) and 20 mltoluene and heated for one and one half hours at 75° C. To this wasadded 2-morpholin-4-ylethylamine (1.2 eq) and the resulting mixture wasstirred at 75° C. overnight. The reaction was then concentrated andpartitioned between ethyl acetate and distilled water. The organic layerwas dried with sodium sulfate and concentrated and titurated with etherthen hexanes to give the purified product. MS: MH⁺=417.

Step 2: Synthesis ofN-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}[(2-morpholin-4-ylethyl)amino]carboxamide

To a flask containingN-{4-[4-(methylamino)-3-nitrophenoxy](2-pyridyl)}[(2-morpholin-4-ylethyl)amino]carboxamidein methanol was added a catalytic amount of 10% Pd/C and hydrogenated toyield in quantitative amountN-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}[(2-morpholin-4-ylethyl)amino]carboxamide.MS: MH⁺=387.

Step 3: Synthesis of 3-(tert-butyl)benzenisothiocyanate

To 3-(tert-butyl)phenylamine in acetone at 0° C. was added sodiumbicarbonate (2 eq) and thiophosgene (2 eq). The mixture was brought toambient temperature and concentrated and partitioned between ethylacetate and water. The organic layer was dried with sodium bicarbonateand sodium sulfate and concentrated to yield3-(tert-butyl)benzenisothiocyanate. MS: MH⁺=192.

Step 4: Synthesis ofN-[4-({2-[(3-tert-butylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N′-(2-morpholin-4-ylethyl)urea

To 3-(tert-butyl)benzenisothiocyanate (1 eq) in methanol was addedN-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}[(2-morpholin-4-ylethyl)amino]carboxamide(1 eq) and the resulting mixture was stirred at ambient temperature for16 h. LC/MS showed formation of corresponding thiourea. To this wasadded anhydrous ferric chloride (1.5 eq) and stirred for 3 h. Thereaction mixture was then concentrated to half its volume and brought toneutral pH with 1N sodium hydroxide. It was then extracted with ethylacetate and the organic layer was washed with brine and dried withsodium sulfate. The crude material was then purified on preparativechromatography to yield N-[4-({2-[(3-tert-butylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N′-(2-morpholin-4-ylethyl)urea.MS: MH⁺=544.

EXAMPLE 24 Synthesis of2-(4-ethylpiperazin-1-yl)-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide

1. Synthesis ofN-(4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-chloroacetamide

A solution of 4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-amine (1 eq)and triethylamine (2 eq) in tetrahydrofuran was treated with2-chloroacetyl chloride and stirred for 15 minutes at room temperature.The reaction mixture was then concentrated and partitioned between ethylacetate and water. The organic layer was separated and washed withbrine, dried over sodium sulfate and concentrated in vacuum to givecrude product. Purification on silica gel with 2% methanol in methylenechloride gaveN-(4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-chloroacetamide asa bright orange solid. HPLC=3.82 min; MS: MH⁺=337.

2. Synthesis ofN-(4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide

The mixture containingN-(4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-chloroacetamide (1eq), 1-ethylpiperazine (3 eq), and potassium carbonate (4 eq) wasstirred in dimethylformamide at 60° C. for 1 hour. The reaction mixturewas then concentrated and partitioned between ethyl acetate and water.The organic layer was separated and washed with water then brine, driedover sodium sulfate and concentrated to give orange solid. Purificationon silica gel with 20% methanol in methylene chloride gaveN-(4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-(4-ethylpiperazin-1-yl)acetamideas a red solid. HPLC=3.26 min; MS: MH⁺=415.

3. Synthesis ofN-(4-(3-amino-4-(methylamino)phenoxy)pyridin-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide

The mixture containingN-(4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-(4-ethylpiperazin-1-yl)acetamidein methanol with a catalytic amount of 10% Pd/C poisoned with lead washydrogenated until the disappearance of the yellow color. The reactionwas then filtered to remove the catalyst and concentrated to yieldN-(4-(3-amino-4-(methylamino)phenoxy)pyridin-2-yl)-2-(4-ethylpiperazin-1-yl)acetamideas a brown oil. HPLC=2.00 min; MS: MH⁺=385.

4. Synthesis of2-(4-ethylpiperazin-1-yl)-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]-amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide

A solution ofN-(4-(3-amino-4-(methylamino)phenoxy)pyridin-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide(1 eq) in methanol was treated with1-fluoro-4-(trifluoromethyl)-2-isothiocyanatobenzene (1 eq) and stirredat room temperature for 16 hours to form the corresponding thiourea. Toit was then added iron (III) chloride (1.2 eq) and stirred for another 4hours. The mixture was then concentrated and partitioned betweensaturated sodium carbonate and ethyl acetate. The organic layer wasseparated and washed with water and brine, dried over sodium sulfate andconcentrated to give brown crude solid. Purification by trituration with5% ethyl acetate in diethyl ether to give2-(4-ethylpiperazin-1-yl)-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamideas tan solid. HPLC=3.40 min; MS: MH⁺=572.

EXAMPLE 25 Synthesis ofN-{4-[(2-{[4-chloro-3-(3-fluoropyridin-4-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide

1. Synthesis of 4-(2-chloro-5-nitrophenyl)-3-fluoropyridine

A mixture of DME: H2O (3:1) was degassed with N₂ for one half hour.2-bromo-1-chloro-4-nitrobenzene (1 eq) added and degassed for another 10minutes. 1,1′-bis(diphenylphosphino)ferrocene palladium(II)chloride(0.05 eq), 3-fluoropyridin-4-yl-4-boronic acid (1 eq), and sodiumcarbonate (3 eq) were then added and stirred at 100° C. for 16 hours.Reaction then concentrated and partitioned between ethyl acetate andwater. Organic layer washed with brine, dried over sodium sulfate andconcentrated. Purification on silica gel, 10% ethyl acetate in hexanesto yield 4-(2-chloro-5-nitrophenyl)-3-fluoropyridine. HPLC=4.57 min; MS:MH⁺=253.

2. Synthesis of 4-chloro-3-(3-fluoropyridin-4-yl)benzenamine

4-(2-chloro-5-nitrophenyl)-3-fluoropyridine (1 eq) was stirred with Iron(0), (3 eq), in acetic acid for 10 hours at room temperature. Reactionneutralized with sodium carbonate and filtered to remove iron. Reactionpartitioned between ethyl acetate and water. Organic layer separated andwashed with brine, dried over sodium sulfate and concentrated to give4-chloro-3-(3-fluoropyridin-4-yl)benzenamine. HPLC=1.72 min; MS:MH⁺=223.

3. Synthesis of 4-(2-chloro-5-isothiocyanatophenyl)-3-fluoropyridine

The mixture containing 4-chloro-3-(3-fluoropyridin-4-yl)benzenamine (1eq) and sodium bicarbonate (2 eq) in acetone was treated withthiophosgene (2 eq) and stirred for 5 minutes at 0° C. Reaction thenconcentrated and partitioned between ethyl acetate and water. Organiclayer dried over sodium sulfate and sodium bicarbonate and concentratedto give 4-(2-chloro-5-isothiocyanatophenyl)-3-fluoropyridine. HPLC=5.54min; MS: MH⁺=265.

4. Synthesis ofN-{4-[(2-{[4-chloro-3-(3-fluoropyridin-4-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide

The mixture containing4-(2-chloro-5-isothiocyanatophenyl)-3-fluoropyridine (1 eq) andN-(4-(3-amino-4-(methylamino)phenoxy)pyridin-2-yl)acetamide (1 eq) inmethanol was stirred at room temperature of 16 hours to give thecorresponding thiourea. To it was then added iron (III) chloride (1.2eq) and stirred for another 4 hours. The mixture was then concentratedand partitioned between saturated sodium carbonate and ethyl acetate.The organic layer was separated and washed with water and brine, driedover sodium sulfate and concentrated to give brown crude solid.Purification on HPLC to yieldN-{4-[(2-{[4-chloro-3-(3-fluoropyridin-4-yl)phenyl]aamino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide.HPLC=3.37 min; MS: MH⁺=503

EXAMPLE 26 Synthesis ofN-[4-({2-[(3-isopropylphenyl)amino]-1,3-benzothiazol-5-yl}oxy)pyridin-2-yl]acetamide

1. Synthesis of N-(3-isopropylphenyl)-5-methoxybenzo[d]thiazol-2-amine

The mixture containing 2-bromo-5-methoxybenzo[d]thiazole (1 eq),3-isopropylbnezylamine (1.5 eq) and diisopropylethylamine (4 eq) wassubjected to microwave in NMP at 235° C. for 15 minutes. Reactionpartitioned between ethyl acetate and water. Organic layer separated andwashed with brine, dried over sodium sulfate and concentrated.Purification on silica gel, 10% ethyl acetate in hexane to giveN-(3-isopropylphenyl)-5-methoxybenzo[d]thiazol-2-amine. HPLC=5.50 min;MS: MH⁺=299.

2. Synthesis of 2-(3-isopropylphenylamino)benzo[d]thiazol-5-ol

N-(3-isopropylphenyl)-5-methoxybenzo[d]thiazol-2-amine was charged withhydrobromic acid (45%) and subjected to microwave at 170° C. for 10minutes. Reaction was then neutralized with sodium carbonate (saturatedsolution) and partitioned between ethyl acetate and water. The organiclayer was separated, washed with brine, dried over sodium sulfate andconcentrated to give 2-(3-isopropylphenylamino)benzo[d]thiazol-5-ol.HPLC=4.63 min; MS: MH⁺=285.

3. Synthesis ofN-[4-({2-[(3-isopropylphenyl)amino]-1,3-benzothiazol-5-yl}oxy)pyridin-2-yl]acetamide

The mixture containing 2-(3-isopropylphenylamino)benzo[d]thiazol-5-ol (1eq), N-(4-chloropyridin-2-yl)acetamide (1.4 eq), potassiumbis(trimethylsilyl)amide (4 eq) and potassium carbonate (1.2 eq) indimethylformamide was subjected to the microwave at 200° C. for 15minutes. The reaction was then partitioned between ethyl acetate andwater. The organic layer was separated, washed with brine, dried oversodium sulfate and concentrated to give the crude product. Purificationon HPLC to yieldN-[4-({2-[(3-isopropylphenyl)amino]-1,3-benzothiazol-5-yl}oxy)pyridin-2-yl]acetamide.HPLC=4.87 min; MS: MH⁺=419.

EXAMPLE 27 Synthesis ofN-4-({2-[(3-tert-butylphenyl)amino]-1,3-benzothiazol-5-yl}oxy)pyridin-2-yl]-1-methylpiperidine-4-carboxamide

1. Synthesis of 1-methylpiperidine-4-carbonyl chloride

A flask was flame dried and placed under a nitrogen atmosphere.1-methylpiperidine-4-carboxylic acid (1 eq) in anhydrous methylenechloride added to flask and cooled to 20° C. in a water bath.Dimethylformamide added, then oxalyl chloride (1.4 eq) in methylenechloride. Reaction refluxed for 2 hours, brought to room temperature,concentrated and azeotroped with toluene to yield1-methylpiperidine-4-carbonyl chloride as a light yellow fluffy solid.MS: MH⁺=162.

2. Synthesis ofN-(4-chloropyridin-2-yl)-1-methylpiperidine-4-carboxamide

A flask was flame dried and placed under a nitrogen atmosphere.1-methylpiperidine-4-carbonyl chloride (1 eq) in anhydrous methylenechloride was added to the flask and brought to 0° C. To this was addedthe solution containing 4-chloropyridin-2-amine (1 eq), anddiisopropylethylamine (5 eq) in anhydrous methylene chloride, which wasstirred for 1 hour at 0° C. Reaction concentrated and partitionedbetween water and ethyl acetate. The organic layer was separated, washedwith brine, dried over sodium sulfate and concentrated to give the crudeproduct. Purification on silica gel, 10% methanol in methylene chlorideto yield N-(4-chloropyridin-2-yl)-1-methylpiperidine-4-carboxamide as aslightly yellow crystal solid. HPLC=2.39 min; MS: MH⁺=254.

3. Synthesis ofN-[4-({2-[(3-tert-butylphenyl)amino]-1,3-benzothiazol-5-yl}oxy)pyridin-2-yl]-1-methylpiperidine-4-carboxamide

The mixture containing 2-(3-tert-butylphenylamino)benzo[d]thiazol-5-ol(1 eq), potassium bis(trimethylsilyl)amide (4 eq), and potassiumcarbonate (1.2 eq) in dimethylformamide was stirred at room temperaturefor 10 minutes.N-(4-chloropyridin-2-yl)-1-methylpiperidine-4-carboxamide (1.4 eq) wasthen added and mixture subjected to microwave at 220° C. for 20 minutes.Reaction partitioned between ethyl acetate and water. Organic layerseparated, washed with brine, dried over sodium sulfate and concentratedto give crude product. Purification by HPLC to yieldN-[4-({2-[(3-tert-butylphenyl)amino]-1,3-benzothiazol-5-yl}oxy)pyridin-2-yl]-1-methylpiperidine-4-carboxamide.HPLC=4.74 min; MS: MH⁺=516.

EXAMPLE 28 Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-6-methoxy-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide

1. Synthesis of4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-2-carboxylic acid

Trifluoroacetic acid was added neat to tert-butyl4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-2-carboxylate andstirred at room temperature for 5 hours. TFA was evaporated, solidproduct azeotroped with toluene then placed under vacuum for 24 hours toyield 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-2-carboxylicacid. HPLC=3.07 min; MS: MH⁺=321

2. Synthesis of4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-2-carboxamide

The mixture containing4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-2-carboxylic acid(1 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2 eq),3H-1,2,3-triazolo[4,5-b]pyridine-3-ol (1.5 eq), and diisopropylamine (5eq) in tetrahydrofuran was stirred at room temperature for 1 hour. Tothis was then added ammonium chloride (2 eq) and the resulting mixturewas stirred together for 48 hours. Reaction concentrated. Purificationon silica gel, 50% acetone in hexanes to yield4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-2-carboxamide as abright yellow solid. HPLC=3.70 min; MS: MH⁺=319.

3. Synthesis of4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridin-2-amine

Liquid bromine (2 eq) was added dropwise to a solution of potassiumhydroxide (10 eq) in water at 0° C.4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-2-carboxamide (1eq) was then added in a small amount of dioxane. Reaction brought toroom temperature for ½ hour then heated to 55° C. for 1 hour showing ared homogenous solution. The reaction was brought back to 0° C. andacetic acid (excess) was added. The mixture was heated at 55° C. for ½hour, cooled to room temperature and sodium carbonate added toneutralize. Reaction was extracted with methylene chloride. Organiclayer washed with brine, dried over sodium sulfate and concentrated toyield 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridin-2-amine as anorange solid. HPLC=3.10 min; MS: MH⁺=292.

4. Synthesis ofN-(4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridin-2-yl)acetamide

Under a nitrogen atmosphere,4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)-pyridin-2-amine (1 eq) anddiisopropylethylamine (4 eq) in methylene chloride was brought to 0° C.Acetyl chloride (1.1 eq) was added dropwise and mixture stirred for 5minutes. Reaction brought to room temperature and water added. Organiclayer washed with brine, dried over sodium sulfate and concentrated toyieldN-(4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridin-2-yl)acetamide.HPLC=3.21 min; MS: MH⁺=333.

5. Synthesis ofN-(4-(5-amino-2-methoxy-4-(methylamino)phenoxy)pyridin-2-yl)acetamide

The mixture containingN-(4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridin-2-yl)acetamide inmethanol with a catalytic amount of 10% Pd/C poisoned with lead washydrogenated until the disappearance of the yellow color. The reactionwas then filtered to remove the catalyst and concentrated to yieldN-(4-(5-amino-2-methoxy-4-(methylamino)phenoxy)pyridin-2-yl)acetamide.HPLC=2.25 min; MS: MH⁺=303.

6. Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-6-methoxy-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide

A solution ofN-(4-(5-amino-2-methoxy-4-(methylamino)phenoxy)pyridin-2-yl)acetamide (1eq) in methanol was treated with1-fluoro-4-(trifluoromethyl)-2-isothiocyanatobenzene (1 eq) and stirredat room temperature for 16 hours to form the corresponding thiourea. Toit was then added iron (III) chloride (1.2 eq) and stirred for another 4hours. The mixture was then concentrated and partitioned betweensaturated sodium carbonate and ethyl acetate. The organic layer wasseparated and washed with water and brine, dried over sodium sulfate andconcentrated to give brown crude solid. Purification by HPLC to yieldN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-6-methoxy-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamideHPLC=3.02 min; MS: MH⁺=490.

EXAMPLE 29 Synthesis ofN-[4-({2-[(3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-piperidin-4-ylacetamide

1. Synthesis of5-(2-aminopyridin-4-yloxy)-N-(3-isopropylphenyl)-1-methyl-1H-benzo[d]imidazol-2-amine

The mixture containing 4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-amine(1 eq) and 1-isopropyl-3-isothiocyanatobenzene (1 eq) in methanol wasstirred at room temperature for 16 hours to form the correspondingthiourea. To it was then added iron (III) chloride (1.2 eq) and stirredfor another 4 hours. The mixture was then concentrated and partitionedbetween saturated sodium carbonate and ethyl acetate. The organic layerwas separated and washed with water and brine, dried over sodium sulfateand concentrated to give brown crude solid. Purification by triturationwith toluene to give5-(2-aminopyridin-4-yloxy)-N-(3-isopropylphenyl)-1-methyl-1H-benzo[d]imidazol-2-amineas brown solid. HPLC=3.63 min; MS: MH⁺=374.

2. Synthesis of tert-butyl4-((4-(2-(3-isopropylphenylamino)-1-methyl-1H-benzo[d]imidazol-5-yloxy)pyridin-2-ylcarbamoyl)methyl)piperidine-1-carboxylate

To a mixture of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (1eq) in N,N-dimethyl formamide and N,N,disopropylethylamine (4 eq) wasadded HATU (2 eq) and the mixture was stirred at ambient temperatureuntil it becomes homogeneous. To it was added5-(2-aminopyridin-4-yloxy)-N-(3-isopropylphenyl)-1-methyl-1H-benzo[d]imidazol-2-amine(1 eq) and 4-(dimethylamino)pyridine (0.05 eq) and the resulting mixturewas stirred at room temperature for 16 h. The reaction mixture was thenconcentrated and partitioned between ethyl acetate and water. Theorganic layer was dried over sodium sulfate and the resulting tert-butyl4-((4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-ylcarbamoyl)methyl)piperidine-1-carboxylatewas purified by HPLC. HPLC=4.63 min; MS: MH⁺=599.

3. Synthesis ofN-[4-({2-[(3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-piperidin-4-ylacetamide

To tert-butyl4-((4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-ylcarbamoyl)methyl)piperidine-1-carboxylate(1 eq) in water and acetonitrile was added trifluoroacetic acid (2 eq)and stirred at room temperature for 16 hours. The resulting solution wasfrozen with liquid nitrogen and the lyophilized sample yieldedN-[4-({2-[(3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-piperidin-4-ylacetamide.HPLC=3.49 min; MS: MH⁺=499.

EXAMPLE 30 Synthesis ofN-[4-({2-[(3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(1-methylpiperidin-4-yl)acetamide

1. Synthesis of5-(2-aminopyridin-4-yloxy)-N-(3-isopropylphenyl)-1-methyl-1H-benzo[d]imidazol-2-amine

The mixture containing 4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-amine(1 eq) and 1-isopropyl-3-isothiocyanatobenzene (1 eq) in methanol wasstirred at room temperature for 16 hours to form the correspondingthiourea. To it was then added iron (III) chloride (1.2 eq) and stirredfor another 4 hours. The mixture was then concentrated and partitionedbetween saturated sodium carbonate and ethyl acetate. The organic layerwas separated and washed with water and brine, dried over sodium sulfateand concentrated to give brown crude solid. Purification by triturationwith toluene to give5-(2-aminopyridin-4-yloxy)-N-(3-isopropylphenyl)-1-methyl-1H-benzo[d]imidazol-2-amineas brown solid. HPLC=3.63 min; MS: MH⁺=374.

2. Synthesis of tert-butyl4-((4-(2-(3-isopropylphenylamino)-1-methyl-1H-benzo[d]imidazol-5-yloxy)pyridin-2-ylcarbamoyl)methyl)piperidine-1-carboxylate

To a mixture of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (1eq) in N,N-dimethyl formamide and N,N,disopropylethylamine (4 eq) wasadded HATU (2 eq) and the mixture was stirred at ambient temperatureuntil it becomes homogeneous. To it was added5-(2-aminopyridin-4-yloxy)-N-(3-isopropylphenyl)-1-methyl-1H-benzo[d]-imidazol-2-amine(1 eq) and 4-(dimethylamino)pyridine (0.05 eq) and the resulting mixturewas stirred at room temperature for 16 h. The reaction mixture was thenconcentrated and partitioned between ethyl acetate and water. Theorganic layer was dried over sodium sulfate and the resulting tert-butyl4-((4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-ylcarbamoyl)methyl)piperidine-1-carboxylatewas purified by HPLC. HPLC=4.63 min; MS: MH⁺=599.

3. Synthesis ofN-(4-(2-(3-isopropylphenylamino)-1-methyl-1H-benzo[d]imidazol-5-yloxy)pyridin-2-yl)-2-(piperidin-4-yl)acetamide

To tert-butyl4-((4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-ylcarbamoyl)methyl)piperidine-1-carboxylate(1 eq) in water and acetonitrile was added trifluoroacetic acid (2 eq)and stirred at room temperature for 16 hours. The resulting solution wasfrozen with liquid nitrogen and the lyophilized sample yieldedN-(4-(2-(3-isopropylphenylamino)-1-methyl-1H-benzo[d]imidazol-5-yloxy)pyridin-2-yl)-2-(piperidin-4-yl)acetamide.HPLC=3.49 min; MS: MH⁺=499.

4. Synthesis ofN-[4-({2-[(3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(1-methylpiperidin-4-yl)acetamide

To the mixture containingN-(4-(2-(3-isopropylphenylamino)-1-methyl-1H-benzo[d]imidazol-5-yloxy)pyridin-2-yl)-2-(piperidin-4-yl)acetamide(1 eq), glacial acetic acid (2 eq), and formaline (7.5 eq) intetrahydrofuran:methanol (1:1) was added sodium cyanoborohydride (2 eq)and stirred at room temperature for one hour. Reaction neutralized withsaturated sodium carbonate solution and extracted with ethyl acetate.The organic layer was washed with brine, dried over sodium sulfate andconcentrated to give crude product. Purification by HPLC to yieldN-[4-({2-[(3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(1-methylpiperidin-4-yl)acetamide.HPLC=3.51 min; MS: MH⁺=513.

EXAMPLE 31 Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]acetamide

Step 1:

L-Prolinol (3.0 eq) was added to a mixture of2-chloro-N-{4-[4-(methylamino)-2-nitrophenoxy](2-pyridyl)}acetamide (1eq) in acetonitrile. The resulting mixture was brought to 60° C. LC/MSshowed quantitative conversion after stirring for 1 hour. The reactionwas concentrated to about half the volume of solvent and thenpartitioned between water and ethyl acetate. The aqueous layer wasextracted 2× with ethyl acetate. The organic layers were combined andwashed with water followed by saturated sodium chloride, dried overmagnesium sulfate and concentrate to yield pure product. MS: MH⁺=402.2.

Step 2:

2-(2-Hydroxymethyl-pyrrolidin-1-yl)-N-[4-(4-methylamino-3-nitro-phenoxy)-pyridin-2-yl]-acetamidewas hydrogenated in methanol in the presence of Pd/C for 4 hours. Thecatalyst was removed via filtration through Celite and filtrate wasconcentrated to giveN-[4-(3-Amino-4-methylamino-phenoxy)-pyridin-2-yl]-2-(2-hydroxymethyl-pyrrolidin-1-yl)-acetamide.MS: MH⁺=372.4.

Step 3:

2-Fluoro-5-(trifluoromethyl)phenyl isothiocyanate was added to asolution ofN-[4-(3-Amino-4-methylamino-phenoxy)-pyridin-2-yl]-2-(2-hydroxymethyl-pyrrolidin-1-yl)-acetamidein methanol. Reaction was stirred at room temperature for 15 hours.Thiourea formation was confirmed by LC/MS. Ferric chloride was added andthe resulting mixture was stirred at room temperature for 4 hours. Aftercyclization was complete by LC/MS the reaction mixture was concentratedand aqueous sodium carbonate was added until basic pH. The reactionmixture was partitioned between ethyl acetate and water. The organiclayer was washed with water then brine, and dried over magnesium sulfateand concentrated. The crude product was purified by reverse phase HPLC.MS: MH⁺=559.3.

EXAMPLE 32 Synthesis of(2S)-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-2-carboxamide

Step 1:

N-Boc homoproline (1.0 eq) was added to a solution of the amino pyridine(1.0 eq), BOP (2.0 eq) and diisopropylethylamine (3.0 eq) in DMF. Thesolution is heated overnight at 60° C. The solution is concentrated on arotovap to about one fourth its original volume, then poured into waterand EtOAc. The layers are separated and the organic is washed with waterand then brine, dried over MgSO₄, filtered, silica added, and thesolution is concentrated. The product is then purified by columnchromatography (gradient of 2% MeOH: DCM ->10% MeOH: DCM) to yield thedesired product MH+=472.5.

Step 2:

The nitroaniline was hydrogenated in methanol in the presence of Pd/Cfor 4 hours. The catalyst was removed via filtration through Celite andfiltrate was concentrated to give phenylenediamine. MS: MH⁺=442.4.

Step 3:

2-Fluoro-5-(trifluoromethyl)phenyl isothiocyanate was added to asolution of phenylenediamine in methanol. Reaction was stirred at roomtemperature for 15 hours. Thiourea formation was confirmed by LC/MS.Ferric chloride was added and the resulting mixture was stirred at roomtemperature for 4 hours. After cyclization was complete by LC/MS thereaction mixture was concentrated and aqueous sodium carbonate was addeduntil basic pH. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with water then brine,and dried over sodium sulfate and concentrated. The protecting group isremoved by treating the crude product with HCl in dioxane for 30 minutesat room temperature whereupon the solvent is removed. The crude productwas purified by reverse phase HPLC. MS: MH⁺=529.5.

EXAMPLE 33 Synthesis ofN-[4-({2-[(2-fluoro-5-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide

Step 1:

5-Bromo-2-fluoronitrobenzene (1.0 eq), 4-pyridylboronic acid (2.0 eq),and [1,1′-bis(diphenylphosphino)ferocene]dichloro palladium (II) complexwith DCM are mixed in ethyleneglycol dimethylether and 2M aqueous sodiumcarbonate (4.0 eq). The solution is purged with argon for 20 minutes andthen heated overnight at 100° C. At this time the reation mixture iscooled and then poured into water and EtOAc. The layers are separatedand the organic is washed with water and then brine, dried over MgSO₄,filtered, silica added, and the solution is concentrated. The product isthen purified by column chromatography (gradient of 1% MeOH: DCM ->10%MeOH: DCM) to yield the desired product. MS: MH⁺=219.2.

Step 2:

The nitrophenyl compound was hydrogenated in methanol in the presence ofPd/C for 4 hours. The catalyst was removed via filtration through Celiteand filtrate was concentrated to give the desired aniline. MS:MH⁺=189.2.

Step 3:

The aniline (1.0 eq) was cooled in a biphasic mixture of dichloromethaneand sodium carbonate (4.0 eq) to 0° C. At this time thiophosgene (1.0eq) was added. The solution was allowed to stir for 30 minutes at whichtime the phases were separated and the organic phase was dried overmagnesium sulfate.

Step 4:

2-fluoro-5-(4-pyridyl)phenyl isothiocyanate was added as a solution indcm to a solution of phenylenediamine in methanol. Reaction was stirredat room temperature for 15 hours. Thiourea formation was confirmed by 1c/ms. Ferric chloride was added and the resulting mixture was stirred atroom temperature for 4 hours. After cyclization was complete by 1 c/msthe reaction mixture was concentrated and aqueous sodium carbonate wasadded until basic ph. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with water then brine,and dried over magnesium sulfate and concentrated. The crude product waspurified by reverse phase HPLC. MS: MH+=469.5.

EXAMPLE 34 Synthesis ofN-[4({2-[(3-tert-butylphenyl)amino]-1-methyl-1-H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-methylpiperidin-1-yl)acetamide

Step 1:

Chloroacetyl chloride (1.4 eq) was added dropwise over 15 minutes to astirring solution of the amino pyridine (1.0 eql) and triethylamine (2.7eq) in THF (1.2 L) at room temperature. After 2 hours LC shows 80%conversion to the desired product with a small amount of startingmaterial and some bis acylated product (<10%) as well. The solution isconcentrated on a rotovap to about one fourth its original volume, thenpoured into water and EtOAc. The layers are separated and the organic iswashed with water and then brine, dried over MgSO₄, filtered, silicaadded, and the solution is concentrated. The product is then purified bycolumn chromatography (gradient of 30% EtOAc: hexanes ->60% EtOAchexanes) to yield the desired product (39% yield).

Step 2:

4-Methylpiperidine (2.8 eq) was added to a mixture of2-chloro-N-{4-[4-(methylamino)-2-nitrophenoxy](2-pyridyl)}acetamide (1eq), and potassium carbonate (3.3 eq) in dimethylformamide. Theresulting mixture was brought to 60° C. LC/MS showed quantitativeconversion after stirring for 1 hour. The reaction was partitionedbetween water and ethyl acetate. The aqueous layer was extracted 2× withethyl acetate. The organic layers were combined and washed with waterfollowed by saturated sodium chloride, dried over sodium sulfate andconcentrated. The crude product was passed through a plug of silica andeluted with 10% methanol/methylene chloride. MS: MH⁺=400.2.

Step 3:

N-{4-[4-(methylamino)-3-nitrophenoxy](2-pyridyl)}-2-(4-methylpiperidyl)acetamidewas hydrogenated in the presence of Pd/C for 4 hours. The catalyst wasremoved via filtration and filtrate was concentrated to giveN-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-2-(4-methylpiperidyl)acetamide.MS: MH⁺=370.2.

Step 4:

3-(tert-Butyl)benzenisothiocyanate was added to a solution ofN-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-2-(4-methylpiperidyl)acetamidein methanol. Reaction was stirred at room temperature for 15 hours.Thiourea formation was confirmed by LC/MS. Ferric chloride was added andthe resulting mixture was stirred at room temperature for 4 hours. Aftercyclization was complete by LC/MS the reaction mixture was concentratedand aqueous sodium carbonate was added until basic pH. The reactionmixture was partitioned between ethyl acetate and water. The organiclayer was washed with water then brine, and dried over sodium sulfateand concentrated. The crude product was purified by reverse phase HPLC.MS: MH+=527.2.

EXAMPLES 35-68

The gylcinamides in Examples 35-68 were synthesized in a manner similarto that described above using the indicated starting materials andreagents.

EXAMPLE 35 Synthesis ofN-[4-({2-[(2-fluoro-5-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-methylpiperidin-1-yl)acetamide

EXAMPLE 36 Synthesis of2-(4-methylpiperidin-1-yl)-N-{4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide

EXAMPLE 37 Synthesis ofN-[4-({2-[(4-fluoro-3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-methylpiperidin-1-yl)acetamide

EXAMPLE 38 Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(4-methylpiperidin-1-yl)acetamide

EXAMPLE 39 Synthesis ofN-{4-[(2-{[2,4-difluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(4-methylpiperidin-1-yl)acetamide

EXAMPLE 40 Synthesis ofN-[4-({2-[(2,4-difluoro-5-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-methylpiperidin-1-yl)acetamide

EXAMPLE 41 Synthesis ofN-[4-({2-[(5-tert-butyl-2-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-methylpiperidin-1-yl)acetamide

EXAMPLE 42 Synthesis ofN˜1˜-[4-({2-[(3-tert-butylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N˜2˜,N˜2˜-diethylglycinamide

EXAMPLE 43 Synthesis ofN˜2˜,N˜2˜-diethyl-N˜1˜-[4-({2-[(2-fluoro-5-isopropylphenyl)1H-benzimidazol-5-yl}oxy)pyridin-2-yl]glycinamide

EXAMPLE 44 Synthesis ofN˜2˜,N˜2˜-diethyl-N˜1˜-{4-[(1-methyl-2-{[4-(trifluorometyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}glycinamide

EXAMPLE 45 Synthesis ofN˜2˜,N˜2˜-diethyl-N˜1˜-[4-({2-[(4-fluoro-3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]glycinamide

EXAMPLE 46 Synthesis ofN˜2˜,N˜2˜-diethyl-N˜1˜-{4-[(2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}glycinamide

EXAMPLE 47 Synthesis ofN˜1˜-[4-({2-[(3-tert-butylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N˜2˜-ethyl-N˜2˜-propylglycinamide

EXAMPLE 48 Synthesis ofN˜2˜-ethyl-N˜1˜-[4-({2-[(2-fluoro-5-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N˜2˜-propylglycinamide

EXAMPLE 49 Synthesis ofN˜2˜-ethyl-N˜1˜-{4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-N˜2˜-propylglycinamide

EXAMPLE 50 Synthesis ofN˜2˜-ethyl-N˜1˜-[4-({2-[(4-fluoro-3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N˜2˜-propylglycinamide

EXAMPLE 51 Synthesis ofN˜2˜-ethyl-N˜1˜-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-N˜2˜-propylglycinamide

EXAMPLE 52 Synthesis ofN˜1˜-{4-[(2-{[2,4-difluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-N˜2˜-ethyl-N˜2˜-propylglycinamide

EXAMPLE 53 Synthesis ofN˜1˜-[4-({2-[(2,4-difluoro-5-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N˜2˜-ethyl-N˜2˜-propylglycinamide

EXAMPLE 54 Synthesis ofN˜1˜-[4-({2-[(5-tert-butyl-2-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N˜2˜-ethyl-N˜2˜-propylglycinamide

EXAMPLE 55 Synthesis ofN-[4-({2-[(5-tert-butyl-2-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-piperidin-1-ylacetamide

EXAMPLE 56 Synthesis ofN-[4-({2-[(2-fluoro-5-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-piperidin-1-ylacetamide

EXAMPLE 57 Synthesis ofN-[4-({2-[(5-tert-butyl-2-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(3,5-dimethylpiperidin-1-yl)acetamide

EXAMPLE 58 Synthesis of2-(3,5-dimethylpiperidin-1-yl)-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide

EXAMPLE 59 Synthesis of2-(3,5-dimethylpiperidin-1-yl)-N-[4-({2-[(4-fluoro-3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide

EXAMPLE 60 Synthesis of2-azetidin-1-yl-N-[4-({2-[(5-tert-butyl-2-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide

EXAMPLE 61 Synthesis of2-azetidin-1-yl-N-{4-[(2-{[3-fluoro-4-(trifluoromethyl)phenyl]amino}-1methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide

EXAMPLE 62 Synthesis of2-azetidin-1-yl-N-[4-({2-[(2-fluoro-5-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide

EXAMPLE 63 Synthesis of2-[4-(dimethylamino)piperidin-1-yl]-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide

EXAMPLE 64 Synthesis of2-[4-(dimethylamino)piperidin-1-yl]-N-[4-({2-[(2-fluoro-5-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide

EXAMPLE 65 Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(4-methoxypiperidin-1-yl)acetamide

Step 1:

1-N-Boc-4-hydroxypiperidine (1.0 eq; O. Takuna, H. Yoshitaka, Y. Kaoru,O. Yoshitaka, M. Hideaki. WO2003018019. Preparation of Substituted2-(1,1-Dioxaperhydro-1,4-thiazepin-7-yl)acetamides for TreatingInflammatory Respiratory Disease) in THF (10 mL) was added to NaH (2.7eq) in THF (20 mL) at 0° C. After 20 min, MeI (1.1 eq) was addeddropwise. This mixture stirred for 2 h and was then quenched with H₂Oand extracted twice with EtOAc. The organic layer was dried over sodiumsulfate and concentrated. MS: MH⁺=216.1 (MH⁺-t-Bu). The material wasdissolved in CH₂Cl₂ and TFA (3:1) and stirred overnight. The solvent wasthen removed by rotory evaporation to give a clear oil. MS: MH⁺=116.0.

EXAMPLE 66 Synthesis ofN-{4-[(2-{[2-chloro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(4-methoxypiperidin-1-yl)acetamide

EXAMPLE 67 Synthesis ofN-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(3-methoxyazetidin-1-yl)acetamide

1-N-Boc-3-hydroxyazetidine (1.0 eq) in THF (10 mL) was added to NaH (2.6eq) in THF (20 mL) at 0° C. After 20 min, MeI (1.1 eq) was addeddropwise. This mixture stirred for 2 h and was then quenched with H₂Oand extracted twice with EtOAc. The organic layer was dried over sodiumsulfate and concentrated. MS: MH⁺=132.1 (MH⁺-t-Bu). The material wasdissolved in CH₂Cl₂ and TFA (3:1) and stirred overnight. The solvent wasthen removed by rotary evaporation to give a clear oil. MS: MH⁺=87.9.

EXAMPLE 68 Synthesis ofN-{4-[(2-{[2-chloro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(3-methoxyazetidin-1-yl)acetamide

EXAMPLE 69 Synthesis ofN-{4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}propanamide

1. Synthesis ofN-[4-(4-Methylamino-3-nitro-phenoxy)-pyridin-2-yl]-propionamide

To a stirring suspension of 71a (1 eq) and iPr₂NEt (1.5 eq) in dioxane(4 mL) was added propionyl chloride (2 eq) and mainainted at rtovernight. Hydrazine (1 eq) was added and stirred for 2 hours. Crudeproduct was concentrated down, and was then partitioned between EtOAcand saturated aqueous Na₂CO₃. The layers were separated and the aqueouslayer was extracted with EtOAc (3×). The combined organic portions werewashed with brine, dried (MgSO4), concentrated, and the resultingresidue was adsorbed onto SiO₂. Purification by flash chromatography(0.5:99.5, 0.75:99.25, 1:99, 2:98, methanol-CH₂Cl₂) gave 310 mg of abright orange solid as 71b: ¹H NMR (300 MHz, CDCl₃) □ 8.35 (br s, 1 H),8.13 (d, J=5.77 Hz, 1 H), 7.91 (d, J=2.74 Hz, 1 H), 7.68 (d, J=2.2 Hz, 1H), 7.38 (dd, J=2.74, 2.75 Hz 1 H), 7.11 (d, J=9.61 Hz, 1 H), 6.68 (dd,J=2.47, 2.47 Hz, 1 H), 3.065 (d, J=3.85 Hz, 3 H), 2.40 (m, 2 H), 1.141(m, 3H).

2. Synthesis ofN-{4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}propanamide

A suspension of propionamide 71b (1 eq) and 10% Pd/C (10 mol %) inmethanol (4 mL) was charged with H₂ and the resulting reaction mixturewas maintained under a H₂ atmosphere for 1 h at rt. The mixture wasfiltered and the remaining solids washed thoroughly with EtOAc andmethanol. The combined organic portions were evaporated to afford 272 mgof a brown residue as the phenylene diamine, which was carried forwardwithout further purification.

The above diamine (1 eq) was dissolved in methanol (2 mL) and4-trifluoromethyl phenylthioisocyanate (1 eq) was added. The reactionwas maintained for 16 h. Pyridine (3 eq) was added to the reaction,followed by ferric chloride (1.1 eq). The resulting dark reactionmixture was maintained at rt for 16 h, then suspended in saturatedaqueous Na₂CO₃ solution, and filtered with Celite. The remaining solidswere washed with EtOAc and the combined filtrate was partitioned andseparated. The aqueous portion was extracted with EtOAc (3×) and thecombined organic portions were washed with brine, dried (MgSO₄), andevaporated. Purification by semi-prep HPLC gave 71c as the TFA salt.LCMS m/z 456.2 (MH⁺), t_(R)=3.21 min.

EXAMPLE 70 Synthesis ofN-(4-{[1-methyl-2-({4-[(trifluoromethyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridin-2-yl)propanamide

Synthesized as described above in Example 69 using4-trifluoromethylphenyl isothiocyanate. LCMS m/z 488.2 (MH⁺), R_(t) 3.72min.

EXAMPLE 71 Synthesis ofN-[4-({2-[(3-tert-butylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]propanamide

Synthesized as described above in Example 69 using 3-tert-butylphenylisothiocyanate. LCMS m/z 444.3 (MH⁺), R_(t) 3.47 min.

EXAMPLE 72 Synthesis ofN-[4-({2-[(4-tert-butylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]propanamide

Synthesized as described above in Example 69 using 4-tert-butylphenylisothiocyanate. LCMS m/z 444.3 (MH⁺), R_(t) 3.52 min.

EXAMPLE 73 Synthesis ofN-[4-({2-[(4-fluoro-3-tetrahydrofuran-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]propanamide

Synthesized as described above in Example 69 using3-(2-fluoro-5-isothiocyanato-phenyl)-tetrahydro-furan. LCMS m/z 476.3(MH⁺), R_(t) 2.73 min.

EXAMPLE 74 Synthesis of2-methoxy-N-{4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide

1. Synthesis of2-Methoxy-N-[4-(4-methylamino-3-nitro-phenoxy)-pyridin-2-yl]-acetamide

To a solution of iPr₂NEt (6 eq) and dry DMF (8 mL) was addedmethoxyacetic acid (2 eq). The resulting solution maintained at rt for30 min, at which time HATU (2.2 eq) was added, and continued stirring atrt for 1 hour. 76a (1 eq) was added, the flask was sealed and theresulting solution was heated to 50° C. overnight. Crude product waspartitioned between EtOAc and water, the layers were separated and theaqueous layer was extracted with EtOAc (3×). The combined organicportions were washed with brine, dried (MgSO4), concentrated, and theresulting residue was adsorbed onto SiO₂. Purification by flashchromatography (0.5:99.5, 0.75:99.25, 1:99, 2:98, methanol-CH₂Cl₂) gave640 mg of a bright orange solid as 76b: ¹H NMR (300 MHz, CDCl₃) □ 8.67(br s, 1 H), 8.15 (d, J=5.76 Hz, 1 H), 8.04 (br s, 1 H), 7.965 (d,J=2.75 Hz, 1 H), 7.807 (d, J=2.2 Hz 1 H), 7.30 (dd, J=2.75, 2.75 Hz, 1H), 6.916 (d, J=9.34 Hz, 1 H), 6.63 (dd, J=2.47, 2.48 Hz, 1 H), 3.98 (s,2 H), 3.48 (s, 3 H), 3.06 (d, J=5.22 Hz, 3 H).

2. Synthesis of2-methoxy-N-{4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide

A suspension of methoxyacetamide 76b (1 eq) and 10% Pd/C (10 mol %) inmethanol (4 mL) was charged with H₂ and the resulting reaction mixturewas maintained under a H₂ atmosphere for 1 h at rt. The mixture wasfiltered and the remaining solids washed thoroughly with EtOAc andmethanol. The combined organic portions were evaporated to afford 272 mgof a brown residue as the phenylene diamine, which was carried forwardwithout further purification.

The above diamine (1 eq) was dissolved in methanol (2 mL) and4-trifluoromethyl phenylthioisocyanate (1 eq) was added. The reactionwas maintained for 16 h. Pyridine (3 eq) was added to the reaction,followed by ferric chloride (1.1 eq). The resulting dark reactionmixture was maintained at rt for 16 h, then suspended in saturatedaqueous Na₂CO₃ solution, and filtered with Celite. The remaining solidswere washed with EtOAc and the combined filtrate was partitioned andseparated. The aqueous portion was extracted with EtOAc (3×) and thecombined organic portions were washed with brine, dried (MgSO₄), andevaporated. Purification by semi-prep HPLC gave 76c as the TFA salt.LCMS m/z 474.2 (MH⁺), t_(R) =2.24 min.

EXAMPLE 75 Synthesis ofN˜2˜-isopropyl-N˜1˜-{4[(1-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}glycinamide

1. Synthesis of{[4-(4-Methylamino-3-nitro-phenoxy)-pyridin-2-ylcarbamoyl]-methyl}-carbamicacid tert-butyl ester

To a solution of iPr₂NEt (4.5 eq) and dry DMF (75 mL) was addedtert-Butoxycarbonylamino-acetic acid (1.5 eq). The resulting solutionmaintained at rt for 30 min, at which time HATU (2 eq) was added, andcontinued stirring at rt for 1 hour. 77a (1 eq) was added, the flask wassealed and the resulting solution was heated to 50° C. overnight. Crudeproduct was partitioned between EtOAc and water, the layers wereseparated and the aqueous layer was extracted with EtOAc (3×). Thecombined organic portions were washed with brine, dried (MgSO4),concentrated, and the resulting residue was adsorbed onto SiO₂.Purification by flash chromatography (0.5:99.5, 0.75:99.25, 1:99, 2:98,methanol-CH₂Cl₂) gave 4.11 g of a bright orange solid as 77b.

2. Synthesis of2-Amino-N-{4-[1-methyl-2-(4-trifluoromethyl-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-acetamide

A suspension of 77b (1 eq) and 10% Pd/C (10 mol %) in methanol (4 mL)was charged with H₂ and the resulting reaction mixture was maintainedunder a H₂ atmosphere for 1 h at rt. The mixture was filtered and theremaining solids washed thoroughly with EtOAc and methanol. The combinedorganic portions were evaporated to afford 380 mg of a brown residue asthe phenylene diamine, which was carried forward without furtherpurification.

The above diamine (1 eq) was dissolved in methanol (2 mL) and4-trifluoromethyl phenylthioisocyanate (1 eq) was added. The reactionwas maintained for 16 h. Pyridine (3 eq) was added to the reaction,followed by ferric chloride (1.1 eq). The resulting dark reactionmixture was maintained at rt for 16 h, then suspended in saturatedaqueous Na₂CO₃ solution, and filtered with Celite. The remaining solidswere washed with EtOAc and the combined filtrate was partitioned andseparated. The aqueous portion was extracted with EtOAc (3×) and thecombined organic portions were washed with brine, dried (MgSO₄), andevaporated.

The above glycine-amide (1 eq was dissolved in CH₂Cl₂ (1 mL) andtrifluoroacetic acid (10 eq) was added. The resulting solution wasmaintained at rt for 16 h. Crude product was concentrated down, and thenneutralized with saturated aqueous Na₂CO₃ solution. The aqueous portionwas extracted with EtOAc (3×) and the combined organic portions werewashed with brine, dried (MgSO₄), and evaporated to give 20 mg of 77c asa brownish semi-solid.

3. Synthesis ofN˜2˜-isopropyl-N˜1˜-{4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]-amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}glycinamide

A solution of 77c (1 eq) and acetone (2 eq) in MeOH (100 μL) wasmaintained at rt for 30 min. NaBH(OAc)₃ (3 eq) was added and resultingsuspension continued stirring for 30 min. Crude product was concentrateddown, then partitioned between EtOAc and water, the layers wereseparated and the aqueous layer was extracted with EtOAc (3×). Thecombined organic portions were washed with brine, dried (MgSO4),concentrated. Resulting residue was dissolved in DSMO and purified onsemi-prep HPLC to give 77d as the TFA salt. LCMS m/z 499.1 (MH⁺), t_(R)=2.00 min.

EXAMPLE 76 Synthesis ofN˜1˜-[4-({2-[(4-fluoro-3-tetrahydrofuran-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N˜2˜-isopropylglycinamide

Synthesized as described above in Example 75 using3-(2-fluoro-5-isothiocyanato-phenyl)-tetrahydro-furan. LCMS m/z 519.2(MH⁺), R_(t) 1.80 min.

EXAMPLE 77 Synthesis ofN˜1˜-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-N˜2˜-isopropylglycinamide

Synthesized as described above in Example 75 using2-fluoro-5-trifluoromethylphenyl isothiocyanate. LCMS m/z 517.3 (MH⁺),R_(t) 2.02 min.

EXAMPLE 78 Synthesis ofN˜1˜-[4-({2-[(4-fluoro-3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N˜2˜-isopropylglycinamide

Synthesized as described above in Example 75 using4-fluoro-3-isopropylphenyl isothiocyanate. LCMS m/z 491.2 (MH⁺), R_(t)2.05 min.

EXAMPLE 79 Synthesis ofN˜1˜-[4-({2-[(2-fluoro-5-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N˜2˜-isopropylglycinamide

Synthesized as described above in Example 75 using2-Fluoro-5-isopropylphenyl isothiocyanate. LCMS m/z 491.2 (MH⁺), R_(t)2.09 min.

EXAMPLE 80 Synthesis ofN˜2˜-cyclopentyl-N˜1˜-[4-({2-[(4-fluoro-3-tetrahydrofuran-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]glycinamide

Synthesized as described above in Example 75 using cyclopropanone and3-(2-fluoro-5-isothiocyanato-phenyl)-tetrahydro-furan. LCMS m/z 545.1(MH⁺), R_(t) 2.86 min.

EXAMPLE 81 Synthesis of 1-isopropylazetidin-3-yl4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-ylcarbamate

Step 1: Synthesis of3-[4-(4-Methylamino-3-nitro-phenoxy)-pyridin-2-ylcarbamoyloxy]azetidine-1-carboxylicacid tert-butyl ester

To a suspension of acid 1 (1 eq.) in dry THF (10 mL) at 0° C. was addedtriethylamine (3.0 eq.) and the resulting reaction was maintained at 0°C. for 45 min to afford a homogenous solution. Diphenylphosphoryl azide(DPPA, 1.1 eq) was added and the reaction was maintained o/n allowingthe cooling bath to expire. The reaction was concentrated and theresulting residue dissolved in CH₂Cl₂. The organic portion was washedwith saturated NaHCO₃ (3×) and the combined aqueous phases wereextracted with CH₂Cl₂. The combined organic portions were dried (MgSO₄),filtered, and concentrated. The remaining residue was suspended intoluene. To this suspension was added N-BOC azetidin-2-ol (1 eq) and thereaction mixture was heated to and maintained at 100° C. for 1 h. Thereaction was then allowed to cool to rt and concentrated. The residuewas dissolved in CH₂Cl₂ and washed with saturated Na₂CO₃ (3×). Thecombined aqueous phases were extracted with CH₂Cl₂ and the combinedorganic layers were washed with Na₂CO₃ and brine, dried (MgSO₄), andevaporated. The crude residue was adsorbed onto SiO₂ and purified byflash chromatography (9:1, 4:1, 2:1, 1:1 hexanes-EtOAc) to furnish 625mg (70%) of a light orange solid as 2: 1H NMR (300 MHz, CDCl₃) δ 9.32(br, s, 1 H), 8.17 (d, J=6.0 Hz, 1 H), 8.06 (br dd, J=5.0, 10.2 Hz, 1H), 7.96 (d, J=2.8 Hz, 1 H), 7.52 (d, J=2.5 Hz, 1 H), 7.30 (dd, J=2.8,9.2 Hz, 1 H), 6.93 (d, J=9.2 Hz, 1 H), 6.57 (dd, J=2.5, 6.0 Hz, 1 H),5.18 (dddd, J=4.4, 4.4, 6.9, 6.9 Hz, 1 H), 4.25 (ddd, J=0.8, 6.9, 10.1Hz, 2 H), 3.94 (ddd, J=0.8, 4.4, 10.1 Hz, 2 H), 3.07 (d, J=5.2 Hz, 3 H),1.43 (br s, 9 H).

Step 2: Synthesis of3-[4-(3-Amino-4-methylamino-phenoxy)-pyridin-2-ylcarbamoyloxy]-azetidine-1-carboxylicacid tert-butyl ester

A suspension of nitroaniline 83b (1 eq.) in dry MeOH (8 mL) was spargedwith argon over 20 min. 10% Pd/C (0.1 eq) was added in one portion andthe reaction vessel sealed with a three-way stopcock fitted with aballoon filled with hydrogen. The reaction mixture was purged withhydrogen and the reaction maintained at rt over 3 h. The reaction wasfiltered through Celite and the filtrate was concentrated to give 474 mg(94%) of a brown residue as 83c. The material was carried forwardwithout further purification: LCMS m/z 430.3 (MH⁺), t_(R) =2.07 min.

Step 3: 1-isopropylazetidin-3-yl4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-ylcarbamate

4-Trifluoromethyl phenylthioisocyanate (1.3 eq.) was added to a solutionof diamine 83c (1 eq.) in dry DME (10 mL) and the reaction wasmaintained at rt for 14 h. Pyridine (3 eq.) was added and the reactioncooled to 0° C. FeCl₃ (1.2 eq.) was added in one portion and theresulting reaction was maintained at 0° C. for 5 min, then at rt for 12h. The reaction was concentrated and partitioned with EtOAc andsaturated Na₂CO₃. The resulting mixture was filtered through Celite andthe remaining solids washed with EtOAc. The combined phases were thenpartitioned and separated. The organic phase was washed with saturatedNa₂CO₃ (3×) and the combined aqueous portions were extracted with EtOAc.The combined organic portions were washed with brine, dried (MgSO₄), andconcentrated. The crude residue was adsorbed onto SiO₂ and purified byflash chromatography (2:1 hexanes-acetone). The resulting material wasdissolved in CH₂Cl₂ (4 mL), treated with TFA (1 mL) and the resultingreaction maintained at rt for 2 h. The reaction was concentrated andpartitioned with CH₂Cl₂ and saturated Na₂CO₃. The organic phase waswashed with saturated Na₂CO₃ (3×) and the combined aqueous portions wereextracted with CH₂Cl₂ (3×). The combined organic phases were dried(MgSO₄) and concentrated. The resulting residue was dissolved in MeOH (2mL) and treated with an excess of acetone and NaB(OAc)₃H. The reactionwas maintained at rt for 14 h and then concentrated. The residue wasthen suspended in EtOAc and washed with aqueous 0.5N HCl solution (3×).The combined acidic aqueous phases were made basic (pH=8) by addition of1N NaOH solution. The resulting cloudy aqueous phase was extracted withEtOAc (3×) and the combined organic portions were dried (MgSO₄) andconcentrated. The resulting residue was further purified by preparativeHPLC and reconstituted as the mono mesylate salt to afford 72 mg of 2 asa white solid: ¹H NMR (300 MHz, CD₃OD) δ 8.10 (d, J=5.9 Hz, 1 H), 7.73(d, J=8.9 Hz, 2 H), 7.69 (d, J=8.9 Hz, 2 H), 7.49 (d, J=8.7 Hz, 1 H),7.38 (d, J=2.2. Hz, 1 H), 7.19 (d, J=2.2 Hz, 1 H), 7.03 (dd, J=2.2 8.7Hz, 1 H), 6.65 (dd, J=2.2, 5.9 Hz, 1 H), 5.19 (m, 1 H), 4.50 (app dd,J=6.8, 11.7 Hz, 2 H), 4.24 (app dd, J=4.9, 11.7 Hz, 2 H), 3.49 (dddd,J=6.6, 6.6, 6.6, 6.6 Hz, 1 H), 2.69 (s, 3 H), 1.24 (d, J=6.6 Hz, 6 H);LCMS m/z 541.1 (MH⁺), t_(R)=2.03 min.

EXAMPLE 82 Synthesis of various intermediates for use in thebenzimidazole ring formation are described in this example. EXAMPLE 82a4-fluoro-3-cyclopentyl-1-nitrobenzene

In a steel pressure vessel with stirbar, sodium acetate (4 eq),tetrabutylammonium bromide (1 eq) and Pd(dppf)Cl₂—CH₂Cl₂ (0.03 eq) weresuspended in DMA (dimethylacetamide, 0.2M). Nitrogen was bubbled through10 minutes, then 2-fluoro-1-iodobenzene (1 eq) and cyclopentene (5 eq)were added. The vessel was sealed and heated at 140° C., 14 hrs. Thevessel was then cooled to RT, the contents were diluted (ethyl acetate),washed successively with water (2×), aq. NaHCO₃, NaCl, then dried overanhydrous K₂CO₃, filtered and stripped to an oil. Chromatography (3%ethyl acetate in hexanes on silica gel) provides a pale green oil as amixture of olefin isomers (83%).

Hydrogenation over palladium on carbon (0.5 gm 10% w/w) in methanol (60mL) at 80 psig and RT converts both to a single, volatile alkane2′fluorophenylcyclopentane.

A solution of 2′fluorophenylcyclopentane in acetic anhydride (0.2M) wascooled to −10° C. Sulfuric acid (to make 1% v/v) was added. Followed bynitric acid (1.15 eq), dropwise. After addition was complete, thereaction was allowed to warm to RT. After 30 min at RT, TLC showedcomplete reaction. The mixture was poured onto ice, extracted into ethylacetate 2×. The combined extracts were washed successively with water,aq. NaHCO₃, NaCl, then dried over anhydrous K₂CO₃, filtered and strippedto an oil. Flash chromatography (3% ethyl acetate in hexanes on silicagel) provides 4-fluoro-3-cyclopentyl-1-nitrobenzene (48% yield)

EXAMPLE 82b Synthesis of 1-tert-butyl-4-fluorobenzene

In a steel bomb were combined 4-tert-butyl aniline (1 eq) and 70%hydrogen fluoride-pyridine (25 g/gm aniline). Sodium nitrite (1.5 eq)was then added portion wise over 5 minutes. The resulting solution wasallowed to stir for 1 h at room temperature and then the bomb was sealedand heated at 85° C. for 1 h. Solution was then quenched with water/iceand extracted with ethyl ether. Organics washed with brine and driedwith sodium sulfate and concentrated to afford1-tert-butyl-4-fluorobenzene.

¹H NMR (DMSO, δ ppm): 1.22(9H, s), 7.07 (2H, t), 7.38 (2H, dd)

EXAMPLE 82c Synthesis of 4-tert-butyl-1-fluoro-2-nitrobenzene

1-tert-butyl-4-fluorobenzene (1 eq) was dissolved in concentratedsulfuric acid (1.65M) and cooled to 0° C. in an ice/water bath.Potassium nitrate(1 eq) was then added in small portions as to allow thetemperature of the reaction not to exceed 7° C. After complete additionthe mixture was allowed to stir for an additional 30 minutes, thenpoured onto ice/water and extracted with ethyl acetate. Organics werewashed with a saturated solution of sodium bicarbonate, brine and driedwith sodium sulfate and concentrated. Crude mixture was purified byflash chromatography on silica.

(85% Hex:15% EtOAc) to afford 4-tert-butyl-1-fluoro-2-nitrobenzene.

¹H NMR (CDCl₃, δ ppm): 1.3(9H, s), 7.2(1H, dd), 7.62(1H, ddd), 8.03(1H,dd)

EXAMPLE 82d Synthesis of 5-tert-butyl-2-fluorobenzenamine

To 4-tert-butyl-1-fluoro-2-nitrobenzene in methanol was added acatalytic amount of palladium on carbon (10%). The mixture was allowedto stir for 1 h at room temperature under an atmosphere of hydrogen.Mixture was filtered though celite and concentrated to afford5-tert-butyl-2-fluorobenzenamine.

MS: MH⁺=168

EXAMPLE 82e Synthesis of 1-(2-fluoro-5-nitrophenyl)ethanone

In a 3-neck flask equipped with an internal thermometer was addedsulfuric acid and cooled to −10° C. in an ice/salt/water batch.2′-fluoroacetophenone(1 eq) in sulfuric acid was added dropwise over 10minutes via addition funnel to produce a solution of 0.2M. Nitric acid(1.15 eq) in sulfuric acid was then added dropwise at a rate not toexceed 5° C. After complete addition resulting solution was allowed tostir at for 30 minutes. Solution was poured onto ice and extracted withethyl acetate. Organics were washed with a saturated solution of sodiumbicarbonate, brine, dried with sodium sulfate and concentrated. Crudeproduct was purified using flash chromatography (85% Hex:15% EtoAc) onsilica to afford 1-(2-fluoro-5-nitrophenyl)ethanone.

¹H NMR (CDCl₃, δ ppm): 2.7(3H,s), 7.28(1H,t), 8.4(1H,m), 8.8(1H,dd)

EXAMPLE 82f Synthesis of 1-fluoro-4-nitro-2-(prop-1-en-2-yl)benzene

KHMDS(1 eq) in toluene is added dropwise over 5 minutes to a stirredsuspension of triphenylphosphinemethyl bromide(1.2 eq) in THF at −78° C.under nitrogen. After complete addition solution is allowed to warm toroom temperature for 5 minutes then cooled a second time to −78° C.1-(2-fluoro-5-nitrophenyl)ethanone(1 eq) in THF is then added viacannulla into the cold suspension over 10 minutes. Resulting mixture isthen allowed to warm to room temperature and stirred for 1 h. Solvent isthen removed under reduced pressure, cyclohexane is then added andmixture heated briefly to reflux, cooled to room temperature, filteredand filtrate concentrated. Crude product is purified using flashchromatography(85% Hex:15% EtoAc) on silica to afford1-fluoro-4-nitro-2-(prop-1-en-2-yl)benzene.

¹H NMR (CDCl₃, δ ppm): 2.15(3H,s), 5.25(2H,d), 7.19(1H,t), 8.1(1H,m),8.2(1H,dd)

EXAMPLE 82g Synthesis 2-(2-fluoro-5-nitrophenyl)-2-methyloxirane

1-fluoro-4-nitro-2-(prop-1-en-2-yl) benzene (1 eq) was dissolved indichloromethane and cooled to −10° C. using and ice/salt/water bathunder nitrogen. MCPBA (1.5 eq) in dichloromethane was then addeddropwise and resulting solution allowed to warm to room temperature andallowed to stir 48 h. Solution was quenched with 10% sodium sulfite,neutralized with saturated solution of sodium bicarbonate, extractedwith dichloromethane. Organics were washed with brine, dried with sodiumsulfate and concentrated. Crude product was purified with flashchromatography (85% Hex: 15% EtoAc) to afford2-(2-fluoro-5-nitrophenyl)-2-methyloxirane.

¹H NMR (CDCl₃, δ ppm): 1.7(3H,s), 2.8(1H, d), 3.05(1H,d), 7.2(1H, t),8.2(1H,m, 8.35(1H,dd)

EXAMPLE 82h Synthesis of 2-(2-fluoro-5-nitrophenyl) propanal

2-(2-fluoro-5-nitrophenyl)-2-methyloxirane (1 eq) was dissolved in ethylether (1 mL) under nitrogen. BF₃-etherate (0.87 eq) was added dropwiseat room temperature and after complete addition solution was allowed tostir for 1 h. Solution was then quenched with water, extracted withethyl ether. Organics washed with brine, dried with sodium sulfate andconcentrated. Crude product was purified using flash chromatography (85%Hex: 15% EtOAc) on silica to afford 2-(2-fluoro-5-nitrophenyl) propanal.

¹H NMR (CDCl₃, δ ppm): 1.5(3H,d), 3.9(1H,c), 7.2(1H,t), 8.15(1H,dd),8.21(1H,m), 9.7(1H,s)

EXAMPLE 82i Synthesis of 2-(2-fluoro-5-nitrophenyl)-2-methylpent-4-enal

To a solution of palladium acetate (0.1 eq), triphenylphosphine (0.2eq), lithium chloride (1.0 eq) in THF were sequentially added2-(2-fluoro-5-nitrophenyl) propanal (1.1 eq) in THF, allyl alcohol (1.0eq), triethylamine (1.2 eq) and triethylborane (2.4 eq) under nitrogenat room temperature. Solution was allowed to stir for 2 h. Mixture wasdiluted with saturated solution of sodium bicarbonate, extracted withethyl acetate. Organics were washed with brine, dried with sodiumsulfate and concentrated. Crude product was purified using flashchromatography (85% Hex: 15% EtoAc) on silica to afford2-(2-fluoro-5-nitrophenyl)-2-methylpent-4-enal.

¹H NMR (CDCl₃, δ ppm): 1.5(3H, s), 2.6-2.85(2H, m), 5.1(2H,m),5.5(1H,m), 7.2(1H,t), 8.2(2H,m), 9.7(1H,d)

EXAMPLE 82j Synthesis of2-(2-fluoro-5-nitrophenyl)-2-methylbutane-1,4-diol

2-(2-fluoro-5-nitrophenyl)-2-methylpent-4-enal(1 eq) was dissolved indichloromethane:methanol (3:1) and cooled to −78° C. Ozone was thenbubbled through the solution until a blue color was noticed. Air wasthen passed through the solution followed by the addition of sodiumborohydride(5 eq). Resulting solution was allowed to warm to roomtemperature and diluted with brine, extracted with dichloromethane.Organics were dried with sodium sulfate and concentrated to afford2-(2-fluoro-5-nitrophenyl)-2-methylbutane-1,4-diol. The product was usedin the next step with no further characterization.

EXAMPLE 82k Synthesis of3-(2-fluoro-5-nitrophenyl)-tetrahydro-3-methylfuran

To a solution of triphenylphosphine(2 eq) in dichloromethane at 0° C.under nitrogen was added dropwise triflic anhydride(1 eq). After 15minutes 2-(2-fluoro-5-nitrophenyl)-2-methylbutane-1,4-diol(1 eq)wasadded in dichloromethane followed by potassium carbonate(1 eq). Theresulting mixture was allowed to warm to room temperature for 5 h. Tothe mixture was added water and extracted with dichloromethane. Theorganic layer was washed with brine and dried with sodium sulfate andconcentrated. Crude product was purified using flash chromatography (85%Hex:15% EtoAc) on silica to afford3-(2-fluoro-5-nitrophenyl)-tetrahydro-3-methylfuran.

¹H NMR (CDCl₃, δ ppm): 1.45(3H,s), 2.2-2.4(2H,m), 3.85(1H,d),3.9-4.05)3H,m), 7.2(1H,t), 8.15(2H,m)

EXAMPLE 82l Synthesis of4-fluoro-3-(tetrahydro-3-methylfuran-3-yl)benzenamine

To 3-(2-fluoro-5-nitrophenyl)-tetrahydro-3-methylfuran in methanol wasadded a catalytic amount of palladium on carbon (10%). The mixture wasallowed to stir for 1 h at room temperature under hydrogen atmosphere.Mixture was filtered though celite and concentrated to afford4-fluoro-3-(tetrahydro-3-methylfuran-3-yl)benzenamine.

MS: MH⁺=196

EXAMPLE 82m Preparation of[4-(4-methylamino-3-nitro-phenoxy)-pyridin-2-yl]carbamic acid ethylester

Ethyl chloroformate (2 eq.) was added to a stirring solution of aniline1 (1 eq.) and iPr₂NEt (2 eq.) in dry THF (14 mL) at 0° C. The reactionwas allowed to warm to rt over 2 h. The reaction concentrated and theresulting residue dissolved in EtOAc. The organic phase was washed withsaturated aqueous NaHCO₃ (3×) and the combined aqueous portions wereextracted with EtOAc. The combined organic portions were concentrated togive an orange residue as 2. The residue was dissolved in DMF (20 mL),hydrazine monohydrate (1 eq.) added and the resulting reactionmaintained at rt for 14 h. The reaction volume was reduced and theremaining solution was partitioned between EtOAc and water. The layerswere separated and the aqueous phase extracted with EtOAc (3×). Thecombined organic layers were concentrated to give an orange solid as 3which was carried forward without further purification: LCMS m/z 333.3(MH⁺), t_(R)=2.29 min.

EXAMPLE 82n Synthesis of4-(3-aminophenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-ol (3)

1 equivalent of known compound 1 (WO 9521452) as a 1M solution in dryTHF was cooled to −20° C. under argon. 1.1 Equivalents of grignardcompound 2 (Aldrich) as a 2M solution in THF was then added dropwise viasyringe. Reaction stirred at −20° C. for 20 mins, allowed to warm toroom temperature, then briefly refluxed.

Solution was then cooled in an ice bath and an excess of dilute aqueousHCl was carefully added. An aqueous solution of sodium bicarbonate wasadded to bring the pH>7 and the product was extracted with ethylacetate. Removal of organic solvent in vacuo gave a residue that waspurified via silica gel column chromatography (30% ethyl acetate inhexane). Compound 3 was then further purified by recrystallizing from ahexane/ethyl acetate solution to give a clear oil in a 75% yield. LCMSm/z 275.3 (MH⁺)

EXAMPLE 82o Synthesis of3-[4-Methoxy-1-(2,2,2-trifluoro-ethyl)-piperidin-4-yl]-phenylamine

To Compound 3 (1 eq) in dry DMF as a 1M solution was added 1.1 eq ofsodium hydride at room temperature. This solution was allowed to reactfor 30 mins. The solution was then cool to 0° C. and 1.1 eq of methyliodine added. Reaction was then slowly warmed to room temperature wherewater was added. The product was extracted with ethyl acetate, washedwith water, dried over magnesium sulfate, and the solvent removed togive Compound 4 in sufficient purity. LCMS m/z 289.3 (MH⁺).

EXAMPLE 82p Synthesis of3-[1-(2,2,2-Trifluoro-ethyl)-piperidin-4-yl]-phenylamine.

Compound 3 was heated to 150° C. in a 6N HCl solution via a microwavereactor for 5 mins. Solution was neutralized and extracted with ethylacetate. After removal of solvent, the intermediate was dissolved inethanol and reduced over PtO in a hydrogen gas atmosphere. The catalystwas removed by filtering through celite and the ethanol evaporated togive Compound 5.

EXAMPLE 82q Synthesis of1-(2,2,2-Trifluoro-ethyl)-piperidine-4-carboxylic acid[4-(4-methylamino-3-nitro-phenoxy)-pyridin-2-yl]-amide

To 1 eq. of Compound 1 in acetone as a 1M solution and 4 eq. Ofpotassium carbonate was added 1 eq of 2,2,2-trifluoromethyltrichloromethansulfonate. Solution briefly refluxed, cooled, solventremoved and residue partitioned between water and ethyl acetate. Organicseparated, dried over magnesium sulfate, solvent evaporated to provide2.

EXAMPLE 83 Synthesis ofN-(4-{[2-({3-[4-fluoro-1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}pyridin-2-yl)acetamide

Compound 85a (1 eq) was dissolved in dichloromethane to a 1M solutionunder argon. DAST (Aldrich), 1 eq., was then added and solution allowedto react for 1 hr.

Water was added, the phases separated, and the organic solvent removedin vacuo. The residue was purified via silica gel column chromatography(5% MeOH/DCM) to give Compound 85b in nearly quantitative yield. LCMSm/z 557.5 (MH⁺), R_(t) 1.61 min.

EXAMPLES 84-515

The compounds in the following Table 1 (Examples 84-515) were similarlysynthesized according to the procedures described in Examples 1-83.

TABLE 1 Ex. Structure Name MH+ 84

N-[4-({2-[(3-isopropyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide416.5 85

N-[4-({2-[(4-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide392.4 86

N-[4-({2-[(3-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide402.5 87

N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide460.4 88

N-[4-({2-[(4-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide402.5 89

N-{4-[(1-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide458.4 90

N-[4-({2-[(4-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide430.5 91

N-[4-({2-[(4-isopropyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide416.5 92

N-[4-({2-[(4-chlorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide408.9 93

N-{4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide476.9 94

N-[4-({2-[(4-isopropyl-3-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide430.5 95

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide465 96

N-[4-({2-[(4-chloro-3-thien-2-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide491 97

N-[4-({2-[(4-bromo-3-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide467.3 98

N-[4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide453.3 99

N-{4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide442.4 100

N-[4-({2-[(4-chlorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]piperidine-4-carboxamide478 101

N-[4-({2-[(4-chlorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-methyl-piperidine-4-carboxamide492 102

N-[4-({2-[(4-chlorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]isonicotinamide471.9 103

N-[4-({2-[(5-chloro-2-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide426.8 104

N-[4-({2-[(5-fluoro-2-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide406.4 105

N-[4-({2-[(2-chloro-5-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide426.8 106

N-[4-({2-[(2-chlorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]acetamide408.9 107

N-[4-({2-[(2,5-difluoro-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide410.4 108

N-[4-({2-[(2,5-dichloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide443.3 109

N-{4-((2-{[2-chloro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide476.9 110

N-[4-({2-[(2-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]acetamide392.4 111

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-methyl-piperidine-4-carboxamide513.7 112

N-[4-({2-[(4-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-pyridin-2-yl]-1-methyl-piperidine-4-carboxamide475.5 113

N-[4-({2-[(3-isopropyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-methyl-piperidine-4-carboxamide499.6 114

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl)aminol-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-methylpiperidine-4-carboxamide548.1 115

N-{4-[(1-methyl-2-{[3-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide442.4 116

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]piperidine-4-carboxamide499.6 117

N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-methyl-piperidine-4-carboxamide543.5 118

N-[4-({2-[(3-isopropyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]piperidine-4-carboxamide485.6 119

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]piperidine-4-carboxamide534.1 120

N-[4-({2-[(4-chloro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]piperidine-4-carboxamide520 121

N-{4-[(1-methyl-2-{[4-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide511.5 122

N-{4-[(2-{[4-chloro-3-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide546 123

N-{4-[(2-{[3-chloro-4-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide546 124

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]-1-isopropyl-piperidine-4-carboxamide541.7 125

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-ethyl-piperidine-4-carboxamide527.7 126

1-ethyl-N-[4-({2-[(3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]piperidine-4-carboxamide513.7 127

1-ethyl-N-[4-({2-[(4-fluoro-3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]piperidine-4-carboxamide531.6 128

N-[4-({2-[(4-chloro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-ethylpiperidine-4-carboxamide548.1 129

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-ethylpiperidine-4-carboxamide562.1 130

1-ethyl-N-{4-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide539.6 131

N-{4-[(2-{[4-chloro-3-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-ethyl-piperidine-4-carboxamide574 132

1-isopropyl-N-[4-({2-[(3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]piperidine-4-carboxamide527.7 133

N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-isopropylpiperidine-4-carboxamide545.7 134

N-[4-({2-[(4-chloro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-isopropylpiperidine-4-carboxamide562.1 135

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-isopropylpiperidine-4-carboxamide576.2 136

N-{4-[(2-{[3-chloro-4-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-ethyl-piperidine-4-carboxamide574 137

N-[4-({2-[(3-isopropyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-3-piperidin-4-ylpropanamide513.7 138

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-3-piperidin-4-ylpropanamide527.7 139

N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-3-piperidin-4-ylpropanamide531.6 140

N-[4-({2-[(4-chloro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-3-piperidin-4-ylpropanamide548.1 141

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-3-piperidin-4-ylpropanamide562.1 142

N-{4-[(2-{[4-chloro-3-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-3-piperidin-4-ylpropanamide574 143

N-{4-[(2-{[4-chloro-3-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-methyl-piperidine-4-carboxamide560 144

N-{4-[(2-{[3-chloro-4-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-methyl-piperidine-4-carboxamide560 145

N-[4-({2-[(4-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-pyridin-2-yl]-1-methyl-piperidine-4-carboxamide485.6 146

N-{4-[(2-{[4-fluoro-3-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-methyl-piperidine-4-carboxamide543.5 147

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-3-(1-methyl-piperidin-4-yl)propanamide541.7 148

N-[4-({2-[(3-isopropyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-3-(1-methyl-piperidin-4-yl)propanamide527.7 149

N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-3-(1-methylpiperidin-4-yl)propanamide545.7 150

N-[4-({2-[(4-chloro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-3-(1-methylpiperidin-4-yl)-propanamide562.1 151

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-3-(1-methylpiperidin-4-yl)-propanamide576.2 152

N-{4-[(2-{[4-chloro-3-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-3-(1-methyl-piperidin-4-yl)-propanamide588 153

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]-1-(2-methoxy-ethyl)piperidine-4-carboxamide557.7 154

N-[4-({2-[(3-isopropyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-(2-methoxy-ethyl)piperidine-4-carboxamide543.7 155

N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-(2-methoxyethyl)piperidine-4-carboxamide561.7 156

N-[4-({2-[(4-chloro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-(2-methoxyethyl)piperidine-4-carboxamide578.1 157

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-(2-methoxyethyl)piperidine-4-carboxamide592.2 158

N-{4-[(2-{[4-chloro-3-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-(2-methoxyethyl)piperidine-4-carboxamide604 159

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-(2-hydroxyethyl)piperidine-4-carboxamide578.1 160

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]-4-morpholin-4-ylbutanamide543.7 161

N-[4-({2-[(3-isopropyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-4-morpholin-4-ylbutanamide529.7 162

N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-4-morpholin-4-ylbutanamide547.6 163

N-[4-({2-[(4-chloro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-4-morpholin-4-ylbutanamide564.1 164

N-(4-({2-[(3-tert-butyl-4-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-4-morpholin-4-ylbutanamide578.1 165

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-(2-hydroxy-ethyl)piperidine-4-carboxamide543.7 166

N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-(2-hydroxyethyl)piperidine-4-carboxamide547.6 167

N-[4-({2-[(3-isopropyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-3-(1-isopropylpiperidin-4-yl)propanamide555.7 168

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-3-(1-isopropylpiperidin-4-yl)-propanamide604.2 169

N~1~-[4-({2-[(3-tert-butyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N~2~-methyl-glycinamide459.6 170

N~1~-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N~2~-methylglycinamide463.5 171

N~1~-[4-({2-[(2-fluoro-5-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N~2~-methylglycinamide463.5 172

N~2~-methyl-N~1~-{4-[(1-methyl-2-{[4-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}glycinamide471.5 173

1-isopropyl-N-{4-[(1-methyl-2-{[4-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide553.6 174

N-[4-({2-[(2,5-difluoro-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-isopropyl-piperazin-1-yl)acetamide536.6 175

2-(4-isopropylpiperazin-1-yl)-N-{4-[(1-methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide568.6 176

N-{4-[(2-{[2-chloro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(4-isopropylpiperazin-1-yl)acetamide603.1 177

N-[4-({2-[(2-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-pyridin-2-yl]-2-(4-isopropyl-piperazin-1-yl)acetamide518.6 178

N~2~-methyl-N~1~-{4-[(1-methyl-2-{[3-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}glycinamide471.5 179

N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-methoxyethyl)piperazin-1-yl]acetamide602.6 180

N-{4-[(2-{[2-chloro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(4-ethyl-piperazin-1-yl)acetamide589 181

N-{4-[(2-{[2-chloro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-methoxyethyl)piperazin-1-yl]acetamide619.1 182

N-{4-[(2-{[2-chloro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide605 183

N-{4-[(2-{[2-chloro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-(2-methoxyethyl)piperidine-4-carboxamide604 184

N-[4-({2-[(3-isopropyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-methyl-piperazin-1-yl)acetamide514.6 185

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-methyl-piperazin-1-yl)acetamide528.7 186

N-[4-({2-[(4-chloro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-methylpiperazin-1-yl)acetamide549.1 187

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-methylpiperazin-1-yl)acetamide563.1 188

N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-methylpiperazin-1-yl)acetamide532.6 189

2-(4-methylpiperazin-1-yl)-N-{4-[(1-methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide540.6 190

N-[4-({2-[(3-isopropyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-pyrrolidin-1-ylacetamide485.6 191

N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-pyrrolidin-1-ylacetamide503.6 192

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-pyrrolidin-1-ylacetamide534.1 193

N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-pyrrolidin-1-ylacetamide529.5 194

N-[4-({2-[(4-chloro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-pyrrolidin-1-ylacetamide520 195

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-pyrrolidin-1-ylacetamide499.6 196

2-[(2R,6S)-2,6-dimethyl-morpholin-4-yl]-N-[4-({2-[(3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide529.7 197

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]acetamide543.7 198

2-[(2R,6S)-2,6-dimethyl-morpholin-4-yl]-N-{4-[(2-{[2-fluoro-5-(tri-fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide573.6 199

2-[(3R,5S)-3,5-dimethyl-piperazin-1-yl]-N-[4-({2-[(3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide528.7 200

2-[(3R,5S)-3,5-dimethyl-piperazin-1-yl]-N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide546.7 201

2-[(2R,6S)-2,6-dimethyl-morpholin-4-yl]-N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide547.6 202

N-[4-({2-[(4-chloro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-[(2R,6S)-2,6-dimethyl-morpholin-4-yl]acetamide564.1 203

2-(3-hydroxyazetidin-1-yl)-N-[4-({2-[(3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]acetamide487.6 204

N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(3-hydroxyazetidin-1-yl)-acetamide505.6 205

N-[4-({2-[(3-isopropyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-piperazin-1-ylacetamide500.6 206

N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-piperazin-1-ylacetamide518.6 207

N-[4-({2-[(4-chloro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-piperazin-1-ylacetamide535.1 208

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]-2-piperazin-1-ylacetamide514.6 209

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl)amino]1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-piperazin-1-ylacetamide549.1 210

N-[4-({2-[(3-isopropyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-piperidin-1-ylacetamide499.6 211

N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-piperidin-1-ylacetamide517.6 212

N-[4-({2-[(4-chloro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-piperidin-1-ylacetamide534.1 213

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]-2-piperidin-1-ylacetamide513.7 214

N-[4-({2-[(3-isopropyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-isopropyl-piperazin-1-yl)acetamide542.7 215

N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-isopropylpiperazin-1-yl)-acetamide560.7 216

N-[4-({2-[(4-chloro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-isopropylpiperazin-1-yl)acetamide577.1 217

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]-2-(4-isopropyl-piperazin-1-yl)acetamide556.7 218

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-isopropylpiperazin-1-yl)acetamide591.2 219

N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(4-isopropylpiperazin-1-yl)acetamide586.6 220

N-{4-[(2-{[3-chloro-4-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(4-isopropylpiperazin-1-yl)-acetamide603.1 221

2-(4-ethylpiperazin-1-yl)-N-[4-({2-[(3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]acetamide528.7 222

N-[4-({2-[(4-chloro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-ethylpiperazin-1-yl)acetamide563.1 223

N-[4-({2-[(3-tert-butyl-phenyl)amino]1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]-2-(4-ethyl-piperazin-1-yl)acetamide542.7 224

N-{4-[(2-{[3-chloro-4-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(4-ethylpiperazin-1-yl)acetamide589 225

2-(4-ethylpiperazin-1-yl)-N-[4-({2-[(4-fluoro-3-isopropylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide546.7 226

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-ethylpiperazin-1-yl)acetamide577.1 227

N-[4-({2-[(3-isopropyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-morpholin-4-ylacetamide501.6 228

N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-morpholin-4-ylacetamide519.6 229

N-[4-({2-[(4-chloro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-morpholin-4-ylacetamide536 230

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]-2-morpholin-4-ylacetamide515.6 231

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-morpholin-4-ylacetamide550.1 232

N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-morpholin-4-ylacetamide545.5 233

2-[(2R,6S)-2,6-dimethyl-morpholin-4-yl]-N-{4-[(1-methyl-2-{[4-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide555.6 234

2-[(2R,6S)-2,6-dimethyl-morpholin-4-yl]-N-{4-[(1-methyl-2-{[4-(trifluoro-methoxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide571.6 235

2-azetidin-1-yl-N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide489.6 236

2-azetidin-1-yl-N-[4-({2-[(3-tert-butylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide485.6 237

2-azetidin-1-yl-N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]pyridin-2-yl}acetamide515.5 238

2-azetidin-1-yl-N-[4-({2-[(2-fluoro-5-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide489.6 239

2-azetidin-1-yl-N-{4-[(1-methyl-2-{[4-(trifluoro-methoxy)phenyl]-amino}-1H-benzimidazol-5-yl)-oxy]pyridin-2-yl}acetamide513.5 240

N-[4-({2-[(2-fluoro-5-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-pyrrolidin-1-ylacetamide503.6 241

N-{4-[(1-methyl-2-{[4-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-pyrrolidin-1-ylacetamide511.5 242

N-{4-[(1-methyl-2-{[4-(trifluoro-methoxy)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-pyrrolidin-1-ylacetamide527.5 243

2-(4-isopropylpiperazin-1-yl)-N-{4-[(1-methyl-2-{[4-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide568.6 244

2-(4-isopropylpiperazin-1-yl)-N-{4-[(1-methyl-2-{[4-(trifluoromethoxy)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide584.6 245

N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(4-methyl-piperazin-1-yl)-acetamide558.5 246

N-[4-({2-[(2-fluoro-5-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-methylpiperazin-1-yl)-acetamide532.6 247

2-(4-methylpiperazin-1-yl)-N-{4-[(1-methyl-2-{[4-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-acetamide540.6 248

2-(4-methylpiperazin-1-yl)-N-{4-[(1-phenyl]amino}-1H-benzimidazol-5-methyl-2-{[4-(trifluoromethoxy)-yl)oxy]pyridin-2-yl}acetamide556.6 249

2-(4-ethylpiperazin-1-yl)-N-{4-[(1-methyl-2-{[4-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide554.6 250

2-(4-ethylpiperazin-1-yl)-N-{4-[(1-methyl-2-{[4-(trifluoromethoxy)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide570.6 251

2-(4-ethylpiperazin-1-yl)-N-{4-[(1-methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide554.6 252

N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(1H-imidazol-1-yl)acetamide526.5 253

N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-piperidin-1-ylacetamide543.5 254

N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(4-methyl-1,4-diazepan-1-yl)acetamide572.6 255

N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(1H-1,2,4-triazol-1-yl)acetamide527.5 256

N-{4-[(2-{[2-chloro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(1H-1,2,4-triazol-1-yl)acetamide543.9 257

N-{4-[(2-{[2-chloro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(4-methyl-piperazin-1-yl)-acetamide575 258

N-{4-[(2-{[2-chloro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(4-methyl-1,4-diazepan-1-yl)-acetamide589 259

2-(4-ethyl-1,4-diazepan-1-yl)-N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-acetamide586.6 260

N-{4-[(2-{[2-chloro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-pyrrolidin-1-ylacetamide546 261

N-{4-[(2-{[4-chloro-3-(2-fluoro-pyridin-4-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]pyridin-2-yl}acetamide503.9 262

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1,3-benzothiazol-5-yl}oxy)pyridin-2-yl]acetamide433.5 263

2-(4-ethylpiperazin-1-yl)-N-[4-({2-[(2-fluoro-5-pyridin-3-yl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide581.7 264

N-[4-({2-[(2-fluoro-5-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide434.5 265

N-{4-[(2-{[2-fluoro-3-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-isopropyl-piperidine-4-carboxamide571.6 266

N-{4-[(2-{[2-fluoro-4-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-isopropyl-piperidine-4-carboxamide571.6 267

piperidin-4-yl4-({2-[(4-fluoro-3-tetrahydrofuran-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-ylcarbamate547.6 268

N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-morpholin-4-ylacetamide519.6 269

(2S)-N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]piperidine-2-carboxamide499.6 270

(2S)-N-[4-({2-[(2-fluoro-5-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]piperidine-2-carboxamide503.6 271

N-[4-({2-[(2-fluoro-5-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-pyrrolidin-1-ylacetamide538.6 272

N-[4-({2-[(2,4-difluoro-5-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-pyrrolidin-1-ylacetamide521.6 273

N-[4-({2-[(2-fluoro-5-pyridin-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]cyclopropanecarboxamide495.5 274

2-(4-ethylpiperazin-1-yl)-N-[4-({2-[(2-fluoro-5-pyridin-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide581.7 275

2-(4-ethylpiperazin-1-yl)-N-[4-({2-[(2-fluoro-5-pyridin-4-ylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide581.7 276

N-[4-({2-[(2-fluoro-5-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]acetamide568.6 277

N-[4-({2-[(2-fluoro-5-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]cyclopropane-carboxamide495.5 278

N-[4-({2-[(2-fluoro-5-pyridin-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-methoxypiperidin-1-yl)acetamide582.6 279

2-[(2R,4R)-2,4-dimethyl-azetidin-1-yl]-N-[4-({2-[(2-fluoro-5-pyridin-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide552.6 280

N-[4-({2-[(2-fluoro-5-pyridin-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide469.5 281

N-[4-({2-[(3-tert-butyl-4-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-pyrrolidin-1-ylacetamide517.6 282

N-[4-({2-[(5-tert-butyl-2-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-pyrrolidin-1-ylacetamide517.6 283

(2S)-N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]paperidine-2-carboxamide503.6 284

N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-piperidin-1-ylacetamide517.6 285

N-[4-({2-[(2-fluoro-5-pyridin-4-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-methoxypiperidin-1-yl)acetamide582.6 286

2-(4-methoxypiperidin-1-yl)-N-{4-[(1-methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide555.6 287

2-(4-methoxypiperidin-1-yl)-N-{4-[(1-methyl-2-{[4-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide555.6 288

N-[4-({2-[(2-fluoro-5-pyridin-4-yl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(3-methoxyazetidin-1-yl)-acetamide554.6 289

2-(3-methoxyazetidin-1-yl)-N-{4-[(1-methyl-2-{[3-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide527.5 290

N-[4-({2-[(5-tert-butyl-2-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(3-methoxyazetidin-1-yl)-acetamide533.6 291

2-(3-methoxyazetidin-1-yl)-N-{4-[(1-methyl-2-{[4-(trifluoromethyl)-phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide527.5 292

2-methoxy-N-(4-{[1-methyl-2-({4-[(trifluoro-methyl)thio]phenyl}amino)-1H-benzimidazol-5-yl]oxy}pyridin-2-yl)acetamide504.5 293

N-[4-({2-[(4-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]-2-methoxy-acetamide432.5 294

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]-2-methoxy-acetamide460.5 295

N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-methoxy-acetamide490.4 296

N-[4-({2-[(4-fluoro-3-tetrahydro-furan-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-methoxy-acetamide492.5 297

N-{4-[(1-methyl-2-{[4-(trifluoro-methyl)phenyl]amino}1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-tetrahydrofuran-3-carboxamide498.5 298

N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl]oxy)pyridin-2-yl]-tetrahydrofuran-3-carboxamide490.5 299

N-[4-({2-[(4-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-pyridin-2-yl]tetrahydro-furan-3-carboxamide458.5 300

N-[4-({2-[(3-tert-butyl-phenyl)amino]1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]tetrahydro-furan-3-carboxamide486.6 301

N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-tetrahydro-furan-3-carboxamide516.5 302

N-[4-({2-[(4-fluoro-3-tetrahydro-furan-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]tetrahydro-furan-3-carboxamide518.6

Ex. Structure Name MH+ 303

N-{4-[(1-methyl-2-{[4-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yI}-tetrahydro-furan-2-carboxamide498.5 304

N-[4-({2-[(4-fluoro-3-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-tetrahydro-furan-2-carboxamide490.5 305

N-[4-({2-[(4-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-pyridin-2-yl]tetrahydro-furan-2-carboxamide458.5 306

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]tetrahydro-furan-2-carboxamide486.6 307

N-{4-[(2-{[2-fluoro-5-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-tetrahydro-furan-2-carboxamide516.5 308

N-[4-({2-[(4-fluoro-3-tetra-hydro-furan-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]tetrahydro-furan-2-carboxamide518.6 309

N-{4-[(1-methyl-2-{[3-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl-tetrahydro-furan-2-carboxamide498.5 310

N-(4-{[1-methyl-2-({4-[(trifluoro-methyl)thio]phenyl}amino)-1H-benzi-midazol-5-yl]oxy}pyridin-2-yl)tetrahydro-furan-2-carboxamide530.5 311

N-[4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)-pyridin-2-yl]tetrahydro-furan-2-carboxamide509.4 312

N-{4-[(1-methyl-2-{[4-(trifluoro-methoxy)phenyl]amino}-1H-benzi-midazol-5-yl)oxy]pyridin-2-yl}-tetrahydro-furan-2-carboxamide514.5 313

N~2~,N~2~-dimethyl-N~1~-{4-[(1-methyl-2-{[4-(trifluoro-methoxy)-phenyl]amino}-1H-benzi-midazol-5-yl)oxy]pyridin-2-yl}glycinamide501.5 314

N~1~-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N~2~,N~2~-dimethylgly-cinamide477.6 315

N~2~,N~2~-dimethyl-N~1~-{4-[(1-methyl-2-{[3-(trifluoro-methyl)-phenyl]amino}-1H-benzi-midazol-5-yl)oxy]pyridin-2-yl}glycinamide485.5 316

N~1~-{4-[(2-{[2-fluoro-5-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-N~2~,N~2~-dimethylgly-cinamide503.5 317

N~1~-[4-({2-[(3-tert-butyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N~2~,N~2~-dimethylgly-cinamide473.6 318

N~1~-[4-({2-[(4-ethyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N~2~,N~2~-dimethylgly-cinamide445.5 319

N-{4-[(1-methyl-2-{[4-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-pyrrolidine-3-carboxamide497.5 320

N-{4-[(2-{[2-fluoro-5-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-pyrrolidine-3-carboxamide515.5 321

N-[4-({2-[(4-fluoro-3-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-pyrrolidine-3-carboxamide489.6 322

N-[4-({2-[(4-fluoro-3-tetra-hydrofuran-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]pyrrolidine-3-carboxamide517.6 323

N-{4-[(1-methyl-2-{(3-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-pyrrolidine-3-carboxamide497.5 324

N-{4-[(1-methyl-2-{[4-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-piperidine-3-carboxamide511.5 325

N-[4-({2-[(2-fluoro-5-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-pyrrolidine-3-carboxamide489.6 326

N-{4-[(1-methyl-2-{[4-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-tetrahydro-2H-pyran-4-carboxamide512.5 327

N-[4-({2-[(4-fluoro-3-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-tetrahydro-2H-pyran-4-carboxamide504.6 328

N-[4-({2-[(2-fluoro-5-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-tetrahydro-2H-pyran-4-carboxamide504.6 329

N-{4-[(2-{[2-fluoro-5-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-tetrahydro-2H-pyran-4-carboxamide530.5 330

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]tetrahydro-2H-pyran-4-carboxamide500.6 331

N-{4-[(2-{[4-chloro-3-(3-furyl)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-acetamide474.9 332

N~1~-[4-({2-[(4-fluoro-3-tetrahydro-furan-3-yl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]glycinamide477.5 333

N~1~-[4-({2-[(3-tert-butyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]glycinamide445.5 334

N~1~-[4-({2-[(4-bromo-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]glycinamide468.3 335

N~1~-{4-[(1-methyl-2-{[3-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}glycinamide457.4 336

N~1~-{4-[(1-methyl-2-{[4-(trifluoro-methoxy)phenyl]amino}-1H-benzi-midazol-5-yl)oxy]pyridin-2-yl}-glycinamide473.4 337

N~1~-{4-[(1-methyl-2-{[4-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-glycinamide457.4 338

N~1~-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-glycinamide475.4 339

N~1~-[4-({2-[(4-ethyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]glycinamide417.5 340

N~1~-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl}-glycinamide449.5 341

N~1~-{4-[(1-methyl-2-{[4-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-L-alaninamide471.5 342

N~1~-{4-[(1-methyl-2-{[3-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-L-alaninamide471.5 343

N~1~-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-L-alaninamide489.4 344

N~1~-[4-({2-[(4-bromo-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N~2~,N~2~-dimethylgly-cinamide496.4 345

N~1~-[4-({2-[(4-fluoro-3-tetrahydro-furan-3-yl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N~2~,N~2~-dimethyl-gly-cinamide505.6 346

N~2~,N~2~-dimethyl-N~1~-{4-[(1-methyl-2-{[4-(trifluoro-methyl)-phenyl]amino}-1H-benzi-midazol-5-yl)oxy]pyridin-2-yl}glycinamide485.5 347

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-L-prolinamide485.6 348

N-[4-({2-[(4-fluoro-3-tetra-hydro-furan-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-L-prolinamide517.6 349

N-[4-({2-[(4-fluoro-3-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-isopropyl-pyrrolidine-3-carboxamide531.6 350

2-(benzyloxy)-N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide536.6 351

2-(benzyloxy)-N-[4-({2-[(4-fluoro-3-tetra-hydrofuran-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide568.6 352

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]-2-hydroxy-acetamide446.5 353

2-hydroxy-N-{4-[(1-methyl-2-{[4-(tri-fluoromethyl)phenyl]amino}-1H-benzi-midazol-5-yl)oxy]pyridin-2-yl}-acetamide458.4 354

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-3-hydroxy-2-(hydroxy-methyl)-2-methyl-propanamide504.6 355

N-[4-({2-[(4-fluoro-3-tetra-hydrofuran-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]-3-hydroxy-2-(hydroxy-methyl)-2-methyl-propanamide536.6 356

3-hydroxy-2-(hydroxy-methyl)-2-methyl-N-{4-[(1-methyl-2-{[4-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-propanamide516.5 357

N-[4-({2-[(4-fluoro-3-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-3-hydroxy-2-(hydroxy-methyl)-2-methylpropanamide508.6 358

N-[4-({2-[(4-fluoro-3-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-cyclopropane-carboxamide460.5 359

N-[4-({2-[(2-fluoro-5-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-cyclopropane-carboxamide460.5 360

N-{4-[(1-methyl-2-{[4-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-cyclopropane-carboxamide468.4 361

N-[4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]cyclopropane-carboxamide456.6 362

1-isopropyl-N-{4-[(1-methyl-2-{[4-(tri-fluoromethyl)phenyl]amino}-1H-benzi-midazol-5-yl)oxy]pyridin-2-yl}piperidine-3-carboxamide553.6 363

1-isopropyl-N-{4-[(1-methyl-2-{[4-(tri-fluoromethyl)phenyl]amino}-1H-benzi-midazol-5-yl)oxy]pyridin-2-yl}pyrrolidine-3-carboxamide539.6 364

(3S)-N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-(2-hydroxy-ethyl)pyrrolidine-3-carboxamide559.5 365

tert-butyl4-({2-[(3-tert-butylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-ylcarbamate488.6 366

methyl4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl-carbamate450.5 367

methyl4-({2-[(3-tert-butyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-ylcarbamate446.5 368

methyl4-({2-[(4-fluoro-3-tetrahydro-furan-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-ylcarbamate478.5 369

methyl4-({2-[(4-bromo-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-ylcarbamate469.3 370

methyl4-{[1-methyl-2-({3-[(trifluoro-methyl)thio]phenyl}amino)-1H-benzi-midazol-5-yl]oxy}pyridin-2-yl-carbamate490.5 371

methyl4-({2-[(4-ethyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-ylcarbamate418.5 372

methyl4-[(1-methyl-2-{[4-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl-carbamate458.4 373

ethyl4-({2-[(3-tert-butyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-ylcarbamate460.5 374

ethyl4-({2-[(4-fluoro-3-tetra-hydro-furan-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-ylcarbamate492.5 375

ethyl4-({2-[(4-fluoro-3-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl-carbamate464.5 376

ethyl4-({2-[(4-bromophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-ylcarbamate483.3 377

ethyl4-({2-[(4-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-ylcarbamate432.5 378

piperidin-4-yl4-({2-[(3-tert-butyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl-carbamate515.6 379

piperidin-4-yl4-({2-[(4-fluoro-3-tetra-hydrofuran-3-ylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-ylcarbamate547.6 380

piperidin-4-yl4-[(1-methyl-2-{[4-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-ylcarbamate527.5 381

piperidin-4-yl4-({2-[(4-fluoro-3-iso-propylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-ylcarbamate519.6 382

piperidin-4-yl4-[(1-methyl-2-{[3-(trifluoro-methyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-ylcarbamate527.5 383

piperidin-4-yl4-[(2-{[2-fluoro-5-(tri-fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]pyridin-2-ylcarbamate545.5 384

1-isopropyl-azetidin-3-yl4-({2-[(4-fluoro-3-iso-propylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-ylcarbamate533.6 385

N-{4-[(2-{[4-chloro-3-(3-methyl-tetra-hydrofuran-3-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]pyridin-2-yl}acetamide493 386

N-[4-({2-[(3-isopropyl-4-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-acetamide430.5 387

N-[4-({2-[(3-cyclopentyl-4-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-acetamide460.5 388

N-{4-[(1-methyl-2-{[3-(pentafluoro-ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-acetamide492.4 389

N-{4-[(2-{[4-fluoro-3-(3-methyl-tetra-hydrofuran-3-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]pyridin-2-yl}acetamide476.5 390

N-{4-[(1-methyl-2-{[4-(pentafluoro-ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-acetamide492.4 391

N-[4-({2-[(4-fluoro-3-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-methyl-piperidine-4-carboxamide517.6 392

1-methyl-N-{4-[(1-methyl-2-{[4-(penta-fluoroethyl)phenyl]amino}-1H-benzi-midazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide575.6 393

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl-amino]-1-methyl-1H-1-ethylpiperidine-4-carboxamide562.1 394

N-[4-({2-[(4-fluoro-3-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-piperidine-4-carboxamide503.6 395

N-{4-[(1-methyl-2-{[4-(pentafluoro-ethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-piperidine-4-carboxamide561.5 396

N-{4-[(2-{[4-fluoro-3-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-piperidine-4-carboxamide529.5 397

N-{4-[(2-{[4-fluoro-3-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-acetamide460.4 398

N-[4-({2-[(4-fluoro-3-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-(2,2,2-tri-fluoroethyl)piperidine-4-carboxamide585.6 399

N-[4-({2-[(4-fluoro-3-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N-methyl-acetamide448.5 400

N-[4-({2-[(2-fluoro-5-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-piperidine-4-carboxamide503.6 401

1-ethyl-N-[4-({2-[(2-fluoro-5-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]piperidine-4-carboxamide531.6 402

N-[4-({2-[(2-fluoro-5-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-isopropyl-piperazin-1-yl)-acetamide560.7 403

2-(4-ethylpiper-azin-1-yl)-N-[4-({2-[(2-fluoro-5-iso-propylphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide546.7 404

N-[4-({2-[(2-fluoro-5-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-acetamide434.5 405

N-[4-({2-[(2-fluoro-5-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-4-morpholin-4-ylbutanamide547.6 406

N-[4-({2-[(2-fluoro-5-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-methyl-piperidine-4-carboxamide517.6 407

2-[(2R,6S)-2,6-dimethyl-morpholin-4-yl]-N-[4-({2-[(2-fluoro-5-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-acetamide547.6 408

N-{4-[(2-{[4-fluoro-3-(3-methyl-tetra-hydrofuran-3-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-isopropyl-piperidine-4-carboxamide587.7 409

N-{4-[(2-{[2,4-difluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-isopropyl-piperidine-4-carboxamide589.6 410

N-[4-({2-[(2-fluoro-5-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-isopropyl-piperidine-4-carboxamide545.7 411

N~1~-{4-[(2-{[4-fluoro-3-(3-methyl-tetrahydro-furan-3-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]pyridin-2-yl}-N~2~,N~2~-dimethylgly-cinamide519.6 412

N~1~-{4-[(2-{[2,4-difluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]pyridin-2-yl}-N~2~,N~2~-dimethylgly-cinamide521.5 413

N~1~-[4-({2-[(2-fluoro-5-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-N~2~,N~2~-dimethylgly-cinamide477.6 414

N-{4-[(2-{[2,4-difluoro-5-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-acetamide478.4 415

N-{4-[(2-{[2,4-difluoro-5-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-ethylpiper-idine-4-carboxamide575.6 416

N~1~-{4-[(2-{[4-fluoro-3-(3-methyl-tetrahydro-furan-3-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]pyridin-2-yl}glycinamide491.5 417

N~1~-{4-[(2-{[2,4-difluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-pyridin-2-yl}glycinamide493.4 418

N~1~-[4-({2-[(2-fluoro-5-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-glycinamide449.5 419

N-[4-({2-[(5-tert-butyl-2-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-isopropyl-piperazin-1-yl)-acetamide574.7 420

N-[4-({2-[(5-tert-butyl-2-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-acetamide448.5 421

N-[4-({2-[(3-tert-butyl-4-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-acetamide448.5 422

N-[4-({2-[(3-tert-butyl-4-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-isopropyl-piperazin-1-yl)-acetamide574.7 423

N-[4-({2-[(3-tert-butyl-4-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-isopropyl-piperidine-4-carboxamide559.7 424

N-[4-({2-[(5-tert-butyl-2-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-isopropyl-piperidine-4-carboxamide559.7 425

N-{4-[(2-{[2-fluoro-4-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(4-isopropyl-piperazin-1-yl)-acetamide586.6 426

N-{4-[(2-{[2-fluoro-5-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(4-methyl-1,4-diazepan-1-yl)-acetamide572.6 427

N-{4-[(2-{[2-fluoro-5-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide588.6 428

N-{4-[(2-{[2-fluoro-3-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(4-isopropyl-piperazin-1-yl)-acetamide586.6 429

N-{4-[(2-{[2-fluoro-3-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-isopropyl-piperidine-4-carboxamide571.6 430

N-{4-[(2-{[2-fluoro-4-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-isopropyl-piperidine-4-carboxamide571.6 431

N-[4-({2-[(5-tert-butyl-2-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-(2-hydroxy-ethyl)piper-idine-4-carboxamide561.7 432

N-{4-[(2-{[2-chloro-4-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-(4-ethyl-piperazin-1-yl)acetamide589 433

N-{4-[(2-{[2-chloro-4-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-isopropyl-piperidine-4-carboxamide588 434

N-[4-({2-[(5-tert-butyl-2-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-ethyl-piperazin-1-yl)acetamide577.1 435

N-[4-({2-[(5-tert-butyl-2-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide576.7 436

N-[4-({2-[(5-tert-butyl-2-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-[4-(2-methoxyethyl)piperazin-1-yl]acetamide590.7 437

N-(4-{[2-({3-[4-hydroxy-1-(2,2,2-tri-fluoroethyl)piperidin-4-yl]-phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}pyridin-2-yl)-acetamide555.5 438

N-(4-{[2-({3-[4-methoxy-1-(2,2,2-tri-fluoroethyl)piperidin-4-yl]-phenyl}amino)-1-methyl-1H-benzimidazol-5-yl]oxy}pyridin-2-yl)-acetamide569.5 439

N-(4-{[1-methyl-2-({3-[1-(2,2,2-tri-fluoroethyl)piperidin-4-yl]-phenyl}amino)-1H-benzi-midazol-5-yl]oxy}pyridin-2-yl)acetamide539.6 440

N-{4-[(1-methyl-2-{[3-(1-methyl-piperidin-4-yl)phenyl]amino}-1H-benzi-midazol-5-yl)oxy]pyridin-2-yl}acetamide471.6 441

N-[4-({2-[(3-tert-butyl-phenyl)amino]methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]-1-(2,2,2-tri-fluoro-ethyl)piperidine-4-carboxamide581.7 442

N-[4-({2-[(4-fluoro-3-tetra-hydro-2H-pyran-4-yl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide476.3 443

N-{4-[(1-methyl-2-{[3-(trifluoro-methoxy)phenyl]amino}-1H-benzi-midazol-5-yl)oxy]pyridin-2-yl}-acetamide458.3 444

N-[4-({1-methyl-2-[(3-tetrahydro-2H-pyran-4-yl-phenyl)amino]-1H-benzi-midazol-5-yl}oxy)pyridin-2-yl]-acetamide458.3 445

(3R)-1-iso-propyl-N-{4-[(1-methyl-2-{[4-(tri-fluoromethyl)phenyl]amino}-1H-benzi-midazol-5-yl)oxy]pyridin-2-yl}pyrrolidine-3-carboxamide359.6 446

(3R)-N-[4-({2-[(4-fluoro-3-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-isopropyl-pyrrolidine-3-carboxamide531.2 447

(3R)-N-[4-({2-[(2-fluoro-5-isopropyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-isopropyl-pyrrolidine-3-carboxamide531.2 448

(3R)-N-[4-({2-[(5-tert-butyl-2-fluoro-phenyl)amino]-1-methyl-1H-benzmidazol-5-yl}oxy)pyridin-2-yl]-1-isopropyl-pyrrolidine-3-carboxamide545.2 449

(3R)-N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-isopropyl-pyrrolidine-3-carboxamide557.1 450

N-[4-({2-[(3-tert-butyl-phenyl)-amino]quinolin-6-yl}oxy)pyridin-2-yl]acetamide427.5 451

N-[4-({2-[(4-chloro-3-pyridin-4-yl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide485.9 452

N-{4-[(1-methyl-2-{[4-(4-methyl-piperazin-1-yl)phenyl]-amino}-1H-benzimidazol-5-yl)-oxy]pyridin-2-yl}acetamide472.6 453

N-[4-({1-methyl-2-[(4-morpholin-4-ylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide459.5 454

N-{4-[(2-{[5-(2-chloro-pyridin-3-yl)-2-fluorophenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]pyridin-2-acetamide503.9 455

N-{4-[(2-{[4-chloro-3-(2-chloro-pyridin-3-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide520.4 456

N-[4-({2-[(3-isopropyl-phenyl)-amino]-1,3-benzoxazol-5-yl}-oxy)pyridin-2-yl]acetamide403.5 457

N-[4-({2-[(3-tert-butyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-4-methylpiper-azine-1-carboxamide514.6 458

N-[4-({2-[(3-tert-butyl-4-chloro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-4-methylpiper-azine-1-carboxamide549.1 459

N-[4-({2-[(4-chloro-3-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-4-methylpiper-azine-1-carboxamide535.1 460

N-[4-({2-[(4-fluoro-3-iso-propyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-4-methylpiper-azine-1-carboxamide518.6 461

N-{4-[(2-{[2-fluoro-5-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-pyridin-2-yl}-4-methylpiper-azine-1-carboxamide544.5 462

N-[4-({2-[(3-tert-butyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]pyrrolidine-3-carboxamide485.6 463

N-[4-({2-[(4-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-isopropyl-piperidine-4-carboxamide513.7 464

N-[4-({2-[(4-fluorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-1-isopropyl-piperidine-4-carboxamide503.6 465

N-[4-({2-[(2,4-difluoro-5-iso-propylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}-oxy)pyridin-2-yl]-2-(4-isopropyl-piperazin-1-yl)acetamide578.7 466

N-[4-({2-[(3-tert-butyli-soxazol-5-yl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide421.5 467

N-{4-[(2-{[2-fluoro-5-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-pyridin-2-yl}-2-(1H-pyrrol-1-yl)-acetamide525.5 468

N-{4-[(2-{[2-chloro-5-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-pyridin-2-carboxamide590.0 469

N-{4-[(2-{[2-fluoro-5-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-pyridin-2-yl}-2-[(3R)-3-hydroxy-pyrrolidin-1-yl]acetamide545.5 470

N-{4-[(2-{[2-chloro-5-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-pyridin-2-yl}-1-isopropyl-piperidine-4-carboxamide588.0 471

2-[(3R)-3-(dimethyl-amino)-pyrrolidin-1-yl]-N-{4-[(2-{[2-fluoro-5-(trifluoro-methyl)-phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide572.6 472

N-{4-[(2-{[2-fluoro-5-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-pyridin-2-yl}-2-[4-(trifluoro-methyl)-1H-imidazol-1-yl]-acetamide594.5 473

N-[4-({2-[(5-tert-butyl-2-fluoro-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(4-methoxy-piperidin-1-yl)-acetamide561.7 474

N-[4-({2-[(3-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(3-methoxy-azetidin-1-yl)acetamide487.6 475

N-[4-({2-[(4-ethylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(3-methoxy-azetidin-1-yl)acetamide487.6 476

N-[4-({2-[(4-tert-butyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(3-methoxy-azetidin-1-yl)-acetamide515.6 477

1-ethyl-4-[2-({4-[(2-{[2-fluoro-5-(tri-fluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)-oxy]pyridin-2-yl}amino)-2-oxo-ethyl]-1-hydroxy-piperazin-1-ium589.6 478

N-{4-[(2-{[2-fluoro-5-(tri-fluoro-methyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-pyridin-2-yl}-2-piperazin-1-yl-acetamide544.5 479

N-(4-{[2-(cyclohexyl-amino)-1-methyl-1H-benzimidazol-5-yl]oxy}pyridin-2-yl)acetamide380.5 480

N-[4-({1-methyl-2-[(1-phenyl-ethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide402.5 481

N-(4-{[2-(mesityl-amino)-1-methyl-1H-benzimidazol-5-yl]-oxy}pyridin-2-yl)acetamide416.5 482

N-[4-({2-[(2,3-dimethyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide402.5 483

N-[4-({2-[(2-furylmethyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide378.4 484

N-[4-({2-[(3,4-dimethoxy-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide434.5 485

N-(4-{[2-(1,1′-biphenyl-2-yl-amino)-1-methyl-1H-benzimidazol-5-yl]oxy}pyridin-2-yl)acetamide450.5 486

N-{4-[(2-{[2-(4-chloro-phenyl)-ethyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide436.9 487

N-(4-{[2-(isobutyl-amino)-1-methyl-1H-benzimidazol-5-yl]-oxy}pyridin-2-yl)acetamide354.4 488

N-(4-{[2-(isopropyl-amino)-1-methyl-1H-benzimidazol-5-yl]-oxy}pyridin-2-yl)acetamide340.4 489

N-[4-({2-[(2-ethyl-6-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide416.5 490

N-[4-({1-methyl-2-[(3,4,5-tri-methoxy-phenyl)amino]-1H-benzi-midazol-5-yl}oxy)pyridin-2-yl]acetamide464.5 491

N-[4-({2-[(3,5-dimethyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide402.5 492

N-[4-({1-methyl-2-[(4-methyl-benzyl)amino]-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide402.5 493

N-[4-({2-[(2-methoxy-5-methyl-phenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide418.5 494

N-[4-({1-methyl-2-[(4-phenoxy-pyridin-3-yl)amino]-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide467.5 495

N-[4-({1-methyl-2-[(5-morpholin-4-ylpyridin-3-yl)amino]-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide460.5 496

N-[4-({1-methyl-2-[(5-methyl-3-phenylisoxazol-4-yl)amino]-1H-benzi-midazol-5-yl}oxy)pyridin-2-yl]acetamide455.5 497

N-[4-({2-[(3,5-dimethyli-soxazol-4-yl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide393.4 498

N-{4-[(1-methyl-2-{[2-(4-methyl-phenyl)ethyl]amino}-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide416.5 499

N-[4-({1-methyl-2-[(2-morpholin-4-ylethyl)amino]-1H-benzi-midazol-5-yl}oxy)pyridin-2-yl]acetamide411.5 500

N-[4-({1-methyl-2-[(2-piperidin-1-ylethyl)amino]-1H-benzi-midazol-5-yl}oxy)pyridin-2-yl]acetamide409.5 501

N-[4-({2-[(cyclohexyl-methyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide394.5 502

N-(4-{[2-(2,3-dihydro-1H-inden-5-yl-amino)-1-methyl-1H-benzimidazol-5-yl]oxy}pyridin-2-yl)acetamide414.5 503

N-[4-({1-methyl-2-[(tetrahydro-furan-2-yl-methyl)amino]-1H-benzi-midazol-5-yl}oxy)pyridin-2-yl]acetamide382.4 504

N-[4-({2-[(2,5-dimethyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide402.5 505

N-[4-({1-methyl-2-[(2,4,5-tri-methylphenyl)amino]-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide416.5 506

N-(4-{[2-(cyclopentyl-amino)-1-methyl-1H-benzimidazol-5-yl]oxy}pyridin-2-yl)acetamide366.4 507

N-[4-({2-[(4-cyclohexyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide456.6 508

N-[4-({1-methyl-2-[(4-phenoxy-phenyl)amino]-1H-benzi-midazol-5-yl}oxy)pyridin-2-yl]acetamide466.5 509

N-[4-({2-[(2-ethoxyphenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide418.5 510

N-[4-({1-methyl-2-[(2-phenyl-ethyl)amino]-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide402.5 511

N-(4-{[1-methyl-2-(pyridin-3-yl-amino)-1H-benzimidazol-5-yl]-oxy}pyridin-2-yl)acetamide375.4 512

N-[4-({2-[(2-isopropyl-phenyl)-amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]acetamide416.5 513

methyl2-[(5-{[2-(acetyl-amino)pyridin-4-yl]oxyl-1-methyl-1H-benzimidazol-2-yl)amino]butanoate398.4 514

N-(5-{[2-(acetylamino)pyridin-4-yl]oxy}-1-methyl-1H-benzi-midazol-2-yl)benzamide402.4 515

methyl4-[(5-{[2-(acetyl-amino)-pyridin-4-yl]oxy}-1-methyl-1H-benzimidazol-2-yl)amino]-benzoate432.4

EXAMPLE 516 Raf/Mek Filtration Assay

Buffers

Assay buffer: 50 mM Tris, pH 7.5, 15 mM MgCl₂, 0.1 mM EDTA, 1 mM DTT

Wash buffer: 25 mM Hepes, pH 7.4, 50 mM sodium pyrophosphate, 500 mMNaCl

Stop reagent: 30 mM EDTA

Materials Raf, active: Upstate Biotech #14-352 Mek, inactive: UpstateBiotech #14-205 ³³P-ATP: NEN Perkin Elmer #NEG 602 h 96 well assayplates: Falcon U-bottom polypropylene plates #35-1190 Filter apparatus:Millipore #MAVM 096 OR 96 well filtration Millipore Immobilon 1 #MAIPNOB plates: Scintillation fluid: Wallac OptiPhase “SuperMix” #1200-439Assay conditions

Raf approximately 120 pM

Mek approximately 60 nM

³³P-ATP 100 nM

Reaction time 45-60 minutes at room temperature

Assay protocol

Raf and Mek were combined at 2× final concentrations in assay buffer (50mM Tris, pH 7.5, 15 mM MgCl₂. 0.1 mM EDTA and 1 mM DTT) and dispensed 15μl per well in polypropylene assay plates (Falcon U-bottom polypropylene96 well assay plates #35-1190. Background levels are determined in wellscontaining Mek and DMSO without Raf.

To the Raf/Mek containing wells was added 3 μl of 10× of a raf kinaseinhibitor test compound diluted in 100% DMSO. The raf kinase activityreaction was started by the addition of 12 μl per well of 2.5× ³³P-ATPdiluted in assay buffer. After 45-60 minutes, the reactions were stoppedwith the addition of 70 μl of stop reagent (30 mM EDTA). Filtrationplates were pre-wetted for 5 min with 70% ethanol, and then rinsed byfiltration with wash buffer. Samples (90 μl) from the reaction wellswere then transferred to the filtration plates. The filtration plateswere washed 6× with wash buffer using Millipore filtration apparatus.The plates were dried and 100 μl per well of scintillation fluid (WallacOptiPhase “SuperMix” #1200-439) was added. The CPM is then determinedusing a Wallac Microbeta 1450 reader.

EXAMPLE 517 ASSAY 2: Biotinylated Raf Screen

In Vitro Raf Screen

The activity of various isoforms of Raf serine/threonine kinases (e.g.,c-Raf, B-Raf and mutant B-Raf (V599E); see, for example, “Mechanism ofActivation of the RAF-ERK Signaling Pathway by Oncogenic Mutations ofB-RAF”, Cell 116: 855-867 (Mar. 19, 2004); and “Dynamic Changes in C-RafPhosphorylation and 14-3-3 Protein Binding in Response to Growth FactorStimulation—Differential Roles Of 14-3-3 Protein Binding Sites”, Journalof Biological Chemistry 279(14): 14074-14086 (Apr. 2, 2004)) can bemeasured by providing ATP, MEK substrate, and assaying the transfer ofphosphate moiety to the MEK residue. Recombinant isoforms of Raf wereobtained by purification from sf9 insect cells infected with a human Rafrecombinant baculovirus expression vector. Recombinant kinase inactiveMEK was expressed in E. coli and labeled with Biotin post purification.For each assay, test compounds were serially diluted in DMSO then mixedwith Raf (0.50 nM) and kinase inactive biotin-MEK (50 nM) in reactionbuffer plus ATP (1 μM). Reactions were subsequently incubated for 2hours at room temperature and stopped by the addition of 0.5M EDTA.Stopped reaction mixture was transferred to a neutradavin-coated plate(Pierce) and incubated for 1 hour. Phosphorylated product was measuredwith the DELFIA time-resolved fluorescence system (Wallac), using arabbit anti-p-MEK (Cell Signaling) as the primary antibody and europiumlabeled anti-rabbit as the secondary antibody. Time resolvedfluorescence was read on a Wallac 1232 DELFIA fluorometer. Theconcentration of each compound for 50% inhibition (IC₅₀) was calculatedby non-linear regression using XL Fit data analysis software.

Using the procedures of Example 517, the compounds of Examples 1-466,468-476 and 478 were shown to have a raf kinase inhibitory activity atan IC₅₀ of less than 10 μM.

While the preferred embodiments of the invention has been illustratedand described, it will be appreciated that various changes can be madetherein without departing from the spirit and scope of the invention.

1. A compound of the formula (I):

wherein, X₁ and X₃ are selected from N and —NR₄—, wherein R₄ is hydrogenor loweralkyl, provided that one of X₁ and X₃ must be N and the other ofX₁ and X₃ must be —NR₄—; X₂ is —NH— or —(CH₂)_(m)—, wherein m is 0, 1,2, 3 or 4; A₁ is substituted or unsubstituted alkyl, cycloalkyl,heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl,heteroaryl, biaryl, heteroarylaryl, or heteroarylheteroaryl; R₁ ishydrogen or substituted or unsubstituted loweralkyl, alkoxyalkyl,loweralkyloxy, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, alkyloxyalkylheterocycloalkyl, heteroarylalkyl,cycloalkyloweralkyl, heterocycloalkylloweralkyl,loweralkylheterocycloalkyl, arylloweralkyl, heteroarylloweralkyl,alkyloxyalkylheterocycloloweralkyl, or heteroarylloweralkyl; R₂ ishydrogen or loweralkyl; each R₃ and R₃′ are independently selected fromhydrogen, halogen, hydroxy, cyano, loweralkyl, or loweralkoxy; and p andq are independently 0, 1, 2 or 3; or a pharmaceutically acceptable saltthereof.
 2. A compound of claim 1 wherein X₁ is —NR₄—.
 3. A compound ofclaim 2 wherein R₄ is hydrogen.
 4. A compound of claim 2 wherein R₄ ismethyl.
 5. A compound of claim 1 wherein X₂ is —NH—.
 6. A compound ofclaim 1 wherein A₁ is selected from the group consisting of substitutedor unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl,pyridylalkyl, pyrimidinylalkyl, heterocyclylcarbonylphenyl,heterocyclylphenyl, heterocyclylalkylphenyl, chlorophenyl, fluorophenyl,bromophenyl, iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl,4-chiorophenyl, alkylbeuzoate, alkoxyphenyl, dialkoxyphenyl,dialkyiphenyl, trialkytphenyl, thiophene, thiophene-2-carboxylate,alkylthiophenyl, trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl,biphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl,alkylbromophenyl, alkylchlorophenyl, alkylfluorophenyl,trifluoromethylchlorophenyl, trifluoromethylbromophenyl indenyl,2,3-dihydroindenyl, tetralinyl, trifluorophenyl,(trifluoromethyl)thiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl,N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl,2,3-dihydroindolyl, 1-aceytl-2,3-dihydroindolyl, cycloheptyl,bicyclo[2.2.1 ]hept-2-yl, hydroxyphenyl, hydroxyalkylphenyl,pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl,4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl,bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl,imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone,anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl,phenylalkylsulfonyl, 9H-fluoren-1-yl, piperidin-1-yl,piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl,pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl,N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl,hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, 1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl.
 7. A compound of claim1 wherein A₁ has the structure:

wherein R₅, R₆, R₇, R₈ and R₉ are independently selected from hydrogen,halo, loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy,haloloweralkyloxy, loweralkylthio, haloloweralkylthio, and substitutedor unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
 8. Acompound of claim 7 wherein R₅, R₆, R₇, R₈ and R₉ are independentlyselected from hydrogen, chloro, fluoro, methyl, ethyl, propyl,iso-propyl, butyl, tert-butyl, cyano, hydroxy, methyloxy,trifluoromethyl, trifluoromethoxy, trifluoromethylthio, acetyl, andsubstituted or unsubstituted phenyl, phenyloxy, furyl,tetrahydrofuranyl, tetrahydropyranyl, pyridinyl,trifluoromethylpiperidinyl, thiophenyl, piperazinyl, and morpholinyl. 9.A compound of claim 1 wherein R₁ has the structure:

wherein n is 0,1,2,3or 4; r is 1 or 2; X₄ is —CH— or N R₁₀ and R₁₂ areindependently selected from hydrogen, halo, loweralkyl, haloloweralkyl,hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkylsulfonyl,haloloweralkylsulfonyl, and substituted or unsubstituted cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; and R₁₁ is hydrogen, loweralkyl,haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy,loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl,heterocycloalkyl, aryl, or heteroaryl.
 10. A compound of claim 9 whereinn is
 1. 11. A compound of claim 9 wherein R₁₀ and R₁₂ are hydrogen orloweralkyl.
 12. A compound of claim 9 wherein R₁₁ is loweralkyl.
 13. Acompound of the formula (II):

wherein, X₂ is —NH— or —(CH₂)_(m)—, wherein m is 0, 1, 2, 3 or 4; A₁ issubstituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl,polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl,heteroarylaryl, or heteroarylheteroaryl; R₁ is hydrogen or substitutedor unsubstituted loweralkyl, alkoxyalkyl, loweralkyloxy, amino,aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocycloalkyl, heteroarylalkyl, cycloalkyloweralkyl,heterocycloalkylloweralkyl, loweralkylheterocycloalkyl, arylloweralkyl,heteroarylloweralkyl, alkyloxyalkylheterocycloloweralkyl, orheteroarylloweralkyl; R₂ is hydrogen or loweralkyl; R₃ is hydrogen,halogen, loweralkyl, or loweralkoxy; and R₄ is hydrogen or loweralkyl ora pharmaceutically acceptable salt thereof.
 14. A compound of claim 13wherein R₄ is hydrogen.
 15. A compound of claim 13 wherein R₄ is methyl.16. A compound of claim 13 wherein X₂ is —NH—.
 17. A compound of claim13 wherein A₁ is selected from the group consisting of substituted orunsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl,pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl,heterocyclylalkylphenyl, chlorophenyl, fluorophenyl, bromophenyl,iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl,alkylbenzoate, alkoxyphenyl, dialkoxyphenyl, dialkylphenyl,trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl,trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl,cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl,alkylchlorophenyl, alkylfluorophenyl, trifluoromethylchlorophenyl,trifluoromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl,trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl,morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl,cyclohexylalkyl, indolyl, 2,3-dihydroindolyl,1-aceytl-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1 ]hept-2-yl,hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl,pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl,adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl,imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone,anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl,phenylalkylsulfonyl, 9H-fluoren-1-yl, piperidin-1-yl,piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl,pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl,N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl,hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl,1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 18.A compound of claim 13 wherein A₁ has the structure:

wherein R₅, R₆, R₇, R₈ and R₉ are independently selected from hydrogen,halo, loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy,haloloweralkyloxy, loweralkylthio, haloloweralkylthio, and substitutedor unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 19.A compound of claim 18 wherein R₅, R₆, R₇, R₈ and R₉ are independentlyselected from hydrogen, chloro, fluoro, methyl, ethyl, propyl,iso-propyl, butyl, tert-butyl, cyano, hydroxy, methyloxy,trifluoromethyl, trifluoromethoxy, trifluoromethylthio, acetyl, andsubstituted or unsubstituted phenyl, phenyloxy, furyl,tetrahydrofuranyl, tetrahydropyranyl, pyridinyl,trifluoromethylpiperidinyl, thiophenyl, piperazinyl, and morpholinyl.20. A compound of claim 13 wherein R₁ has the structure:

wherein n is 0, 1, 2, 3or4; r is 1 or 2; X₄ is —CH— or N R₁₀ and R₁₂ areindependently selected from hydrogen, halo, loweralkyl, haloloweralkyl,hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkylsulfonyl,haloloweralkylsulfonyl, and substituted or unsubstituted cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; and R₁₁ is hydrogen, loweralkyl,haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy,loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl,heterocycloalkyl, aryl, or heteroaryl.
 21. A compound of claim 20wherein n is
 1. 22. A compound of claim 20 wherein R₁₀ and R₁₂ arehydrogen or loweralkyl.
 23. A compound of claim 20 wherein R₁₁ isloweralkyl.
 24. A compound of the formula (IV):

wherein X₁ is —NR₄—, wherein R₄ is hydrogen or loweralkyl; A₁ issubstituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl,polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl,heteroarylaryl, or heteroarylheteroaryl; R₁ is hydrogen or substitutedor unsubstituted loweralkyl, alkoxyalkyl, loweralkyloxy, amino,aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkyloxyalkylheterocycloalkyl, heteroarylalkyl, cycloalkyloweralkyl,heterocycloalkylloweralkyl, loweralkylheterocycloalkyl, arylloweralkyl,heteroarylloweralkyl, alkyloxyalkylheterocycloloweralkyl, orheteroarylloweralkyl; R₂ is hydrogen or loweralkyl; and R₃ is hydrogen,halogen, loweralkyl, or loweralkoxy; or a pharmaceutically acceptablesalt thereof.
 25. A compound of claim 24 wherein R₄ is hydrogen.
 26. Acompound of claim 24 wherein R₄ is methyl.
 27. A compound of claim 24wherein A₁ is selected from the group consisting of substituted orunsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl,pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl,heterocyclylalkylphenyl, chlorophenyl, fluorophenyl, bromophenyl,iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl,alkylbenzoate, alkoxyphenyl, dialkoxyphenyl, dialkylphenyl,trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl,trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl,cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl,alkylchlorophenyl, alkylfluorophenyl, trifluoromethylchlorophenyl,trifluoromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl,trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl,morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl,cyclohexylalkyl, indolyl, 2,3-dihydroindolyl,1-aceytl-2,3-dihydroindolyl, cycloheptyl, bicyclo [2.2.1]hept-2-yl,hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl,pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl,adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl,imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone,anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl,phenylalkylsulfonyl, 9H-fluoren-1-yl, piperidin-1-yl,piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl,pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl,N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl,hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl,1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 28.A compound of claim 24 wherein A₁ has the structure:

wherein R₅, R₆, R₇, R₈ and R₉ are independently selected from hydrogen,halo, loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy,haloloweralkyloxy, loweralkylthio, haloloweralkylthio, and substitutedor unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 29.A compound of claim 24 wherein R₅, R₆, R₇, R₈ and R₉ are independentlyselected from hydrogen, chloro, fluoro, methyl, ethyl, propyl,iso-propyl, butyl, tert-butyl, cyano, hydroxy, methyloxy,trifluoromethyl, trifluoromethoxy, trifluoromethylthio, acetyl, andsubstituted or unsubstituted phenyl, phenyloxy, furyl,tetrahydrofuranyl, tetrahydropyranyl, pyridinyl,trifluoromethylpiperidinyl, thiophenyl, piperazinyl, and morpholinyl.30. A compound of claim 24 wherein R₁ has the structure:

wherein n is 0, 1, 2, 3 or 4; r is 1 or 2; X₄ is —CH— or N R₁₀ and R₁₂are independently selected from hydrogen, halo, loweralkyl,haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, halotoweralkyloxy,loweralkylsulfonyl, haloloweralkylsulfonyl, and substituted orunsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and R₁₁is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl,loweralkyloxy, haloloweralkyloxy, loweralkyloxyloweralkyl, andsubstituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, orheteroaryl.
 31. A compound of claim 30 wherein n is
 1. 32. A compound ofclaim 30 wherein R₁₀ and R₁₂ are hydrogen or loweralkyl.
 33. A compoundof claim 30 wherein R₁₁ is loweralkyl.
 34. A compound of the formula(V):

wherein R₁ is hydrogen or substituted or unsubstituted loweralkyl,alkoxyalkyl, loweralkyloxy, amino, aminoalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocycloalkyl,heteroarylalkyl, cycloalkyloweralkyl, heterocycloalkyl-loweralkyl,loweralkylheterocycloalkyl, arylloweralkyl, heteroarylloweralkyl,alkyloxy-alkylheterocycloloweralkyl, or heteroarylloweralkyl; R₂ ishydrogen or loweralkyl; R₃ is hydrogen, halogen, loweralkyl, orloweralkoxy; R₄ is hydrogen or loweralkyl; and R₅, R₆, R₇, R₈ and R₉ areindependently selected from hydrogen, halo, loweralkyl, cyano, hydroxy,haloloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkylthio,haloloweralkylthio, and substituted or unsubstituted cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; or a pharmaceutically acceptablesalt thereof.
 35. A compound of claim 34 wherein R₄ is hydrogen.
 36. Acompound of claim 34 wherein R₄ is methyl.
 37. A compound of claim 34wherein R₅, R₆, R₇, R₈ and R₉ are independently selected from hydrogen,chloro, fluoro, methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl,cyano, hydroxy, methyloxy, trilluoromethyl, trifluoromethoxy,trifluoromethylthio, acetyl, and substituted or unsubstituted phenyl,phenyloxy, furyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl,trifluoromethylpiperidinyl, thiophenyl, piperazinyl, and morpholinyl.38. A compound of claim 34 wherein R₁ has the structure:

wherein n is 0, 1, 2, 3 or 4; r is 1 or 2; X₄ is —CH— or N R₁₀ and R₁₂are independently selected from hydrogen, halo, loweralkyl,haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy,loweralkylsulfonyl, haloloweralkylsulfonyl, and substituted orunsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and R₁₁is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl,loweralkyloxy, haloloweralkyloxy, loweralkyloxyloweralkyl, andsubstituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, orheteroaryl.
 39. A compound of claim 38 wherein n is
 1. 40. A compound ofclaim 38 wherein R₁₀ and R₁₂ are hydrogen or loweralkyl.
 41. A compoundof claim 38 wherein R₁₁ is loweralkyl.
 42. A compound of the formula(VI):

R₂ is hydrogen or loweralkyl; R₃ is hydrogen, halogen, loweralkyl, orloweralkoxy; R₄ is hydrogen or loweralkyl; and R₅, R₆, R₇, R₈ and R₉ areindependently selected from hydrogen, halo, loweralkyl, cyano, hydroxy,haloloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkylthio,haloloweralkylthio, and substituted or unsubstituted cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; n is 0, 1, 2, 3 or 4; R₁₀ and R₁₂are independently selected from hydrogen, halo, loweralkyl,haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy,loweralkylsulfonyl, haloloweralkyl sulfonyl, and substituted orunsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and R₁₁is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl,loweralkyloxy, haloloweralkyloxy, loweralkyloxyloweralkyl, andsubstituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, orheteroaryl or a pharmaceutically acceptable salt thereof.
 43. A compoundof claim 42 wherein R₄ is hydrogen.
 44. A compound of claim 42 whereinR₄ is methyl.
 45. A compound of claim 42 wherein R₅, R₆, R₇, R₈ and R₉are independently selected from hydrogen, chloro, fluoro, methyl, ethyl,propyl, iso-propyl, butyl, tert-butyl, cyano, hydroxy, methyloxy,trifluoromethyl, trifluoromethoxy, trifluoromethylthio, acetyl, andsubstituted or unsubstituted phenyl, phenyloxy, furyl,tetrahydrofuranyl, tetrahydropyranyl, pyridinyl,trifluoromethylpiperidinyl, thiophenyl, piperazinyl, and morpholinyl.46. A compound of claim 42 wherein n is
 1. 47. A compound of claim 42wherein R₁₀ and R₁₂ are hydrogen or loweralkyl.
 48. The compound ofclaim 42 which is2-(4-ethylpiperazin-1-yl)-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2yl}acetamide.